Antibacterial substituted 7-acylamino-3-(methylhydrazono) methyl-cephalosporins and intermediates

ABSTRACT

A compound of formula  
                 
 
wherein W, V, R 1 , R 5 , R 2 , R 3  and R 4  have various meanings, a process for their production and their use as a pharmaceutical.

The present invention relates to antimicrobial cephalosporins.

In one aspect the present invention provides a compound of formula

whereinR₁ denotes hydrogen, acyl, carboxyl, or alkyl;R₂ and R₃ are the same or different and independently of each otherdenote hydrogen, cycloalkyl, alkyl, alkenyl or alkinyl;R₄ denotes hydrogen or a group of formula

wherein R₆ denotes amino, hydrazino, aminoalkylamino, alkoxy, aryl,cycloalkyl, aryloxy, heterocyclyl,alkyl, alkenyl, alkinyl;R₅ denotes hydrogen or an ester moiety;W denotes CH or N;V denotes CH or N—O; andZ denotes O, S or NR₇, wherein R₇ is as defined as R₂;with the proviso that not all of R₂, R₃ and R₄ denote hydrogen; and,if R₄ denotes hydrogen, R₁ is other than H or CH₃.

A compound of formula I includes a compound of formula

wherein W and R₅ are as defined above,R′₁ denotes hydrogen or alkyl by e.g. including unsubstituted alkyl,e.g.(C₁₋₁₂)alkyl, such as lower alkyl; or substituted alkyl by e.g.halogen, carboxy; e.g. hydrogen or CH₂F;R′₂ and R′₃ are the same or different and independently of each otherdenote hydrogen; alkenyl; e.g. (C₂₋₄)alkenyl; or alkyl;e.g. unsubstituted or substituted by e.g. halogen, aryl; preferablyaryl; including unsubstituted aryl, or aryl substituted by e.g. alkoxy,such as C(₁₋₄)alkoxy or hydroxy; e.g.R′₂ denotes hydrogen, alkyl, or alkenyl; andR′₃ denotes hydrogen or alkyl; andR′₄ denotes hydrogen or a group of formula

whereinZ′ denotes O or NR′₇, wherein R′₇ denotes hydrogen or alkyl, e.g. loweralkyl; andR′₆ denotes amino, including e.g.(di)lower alkylamino; aminoalkylamino,including e.g ((di)lower alkyl)amino-(lower)alkylamino; hydrazino;alkoxy, e.g. lower alkoxy; unsubstituted aryl or aryl substituted e.g.by (lower alkyl)carbonyloxy, lower alkoxy; cycloalkyl; a 5 to 6membered, heterocycle containing 1 to 3 nitrogen and/or sulphur- and/oroxygen atoms, e.g. 1 to 3 nitrogen atoms such as pyrrolidinyl;alkyl, alkenyl, alkinyl including alkyl, alkenyl, alkinyl interrupted byN, S and/or O; e.g. unsubstituted alkyl, alkenyl, alkinyl or substitutedalkyl, alkenyl, alkinyl by hydroxy, aryl, hydroxyaryl, guanidino,nitroguanidino, alkoxy, aryloxy, acyloxy, carbamoyloxy, amino,alkylamino, dialkylamino, trialkylammonium, acylamino, ureido,alkoximino, oximino, imino, carboxy, oxo, halogen, nitro, a carboxylicacid derivative, a sulphonic acid derivative, or heterocyclyl;such as alkyl, e.g. substituted alkyl, e.g. one or several-fold; byunsubstituted aryl, or substituted aryl by hydroxy, alkoxy, phenoxy;aryloxy, e.g. phenoxy; amino, including e.g. (di)lower alkylamino;hydroxy; carboxy; guanidino or nitroguanidino; or aheterocyclylcarboximino group; with the proviso that not all of R₂, R₃and R₄ denote hydrogen.

If not otherwise defined herein any aliphatic group defined hereinincludes an aliphatic group containing up to 20, e.g. 12, such as 8C-atoms. Acyl includes aliphatic or aromatic acyl. Lower alkyl includes(C₁₋₄)alkyl. Aryl includes aryl containing up to 18, e.g. 12 C atoms,including e.g. phenyl, napthyl. Cycloalkyl includes (C₃₋₈)cycloalkyl,such as (C₃₋₆)cycloalkyl.

Heterocyclyl includes e.g. saturated or (partially) unsaturatedheterocyclyl having 5 or 6 ring members and 1 to 5, e.g. 1 to 3 nitrogenand/or 1 to 3 sulphur and/or oxygen hetero atoms including, for example,condensed heterocyclyl, such as benzthiazolyl. Any group as defined maybe unsubstituted or substituted, e.g. by groups which are conventionalgroups in β-lactam chemistry. Substituted heterocyclyl includespreferably substituted heterocyclyl by amino, hydroxy, alkoxy, acyloxy,carboxy or mercapto. An ester-moiety includes alkyl, preferablyC₁₋₆alkyl, e.g. C₁₋₄alkyl; aralkyl, for example benzyl, alkoxybenzyl,such as 4-methoxybenzyl; indanyl, phthalidyl, alkoxymethyl, e.g.methoxymethyl; (C₁₋₆)alkanoyloxy(C₁₋₆)alkyl,(C₁₋₆)alkoxy-carbonyl-oxy(C₁₋₆)alkyl, glycyloxymethyl,phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; anester moiety also includes ester moieties which form with the COO— groupa physiologically hydrolysable and acceptable ester, e.g. such known tobe hydrolysable ester groups in the field of cephalosporins. A compoundof formula I may thus be in the form of an physiologically-hydrolysableand -acceptable ester. By physiologically-hydrolysable and -acceptableesters as used herein is meant an ester in which the COO— group isesterified and which is hydrolysable under physiological conditions toyield an acid which is itself physiologically tolerable at dosages to beadministered. The term is thus to be understood as defining regularpro-drug forms. An ester moiety may be preferably a group which iseasily hydrolysable under physiological conditions. Such esters may beadministered preferably orally. Parenteral administration may beindicated if the ester per se is an active compound or, if hydrolysisoccurs in the blood. A silyl group includes a silyl protecting group,e.g. a conventional silyl protecting group, such as a trialkylsilylgroup, for example the trimethylsilyl group. A leaving group includese.g. a leaving group which is conventional in a type of reactiondescribed; in an acylation reaction of an amine group e.g. a carboxylicacid derivative, such as a carboxylic acid halogenide, (active) ester,(mixed) anhydride) may be an appropriate acylation agent. A cationincludes a cation which may form a pharmaceutically acceptable salt witha compound of formula I; e.g. a metal salt such as sodium, potassium; oran amine (ammonium) salt, such as trialkylamine, procain, dibenzylamine,benzylamine, ammonium salt.

A compound of formula I includes a compound of formula

whereinR₅ is as defined above;R_(2s) and R_(3s) independently of each other denote alkyl, e.g.C₁₋₆alkyl, such as lower alkyl; cycloalkyl, aralkyl, e.g. ar(C₁₋₆)alkyl,such as ar(C₁₋₄)alkyl; aryl; alkenyl, e.g. (C₂₋₆)alkenyl, such as (C₂₋₄)alkenyl; or alkinyl; and R_(3s) additionally denotes hydrogen; e.g.R_(2s) denotes alkyl, alkenyl or aralkyl; e.g. R_(3s) denotes hydrogenor alkyl; e.g. a compound of formula

wherein R₅ is as defined above.

A compound of formula I includes a compound of formula

wherein R₁, R₅, W and V are as defined above,R_(2p) and R_(3p) are the same or different and independently of eachother denote hydrogen, cycloalkyl, or substituted alkyl by halogen orhydroxy,R_(6p) denotes amino, unsubstituted or substituted alkylamino ordialkylamino, alkoxy, aryl, cycloalkyl, aryloxy, an unsubstituted, 5- or6-membered, saturated, partially saturated or unsaturated heterocyclewhich may be condensed containing 1 to 5 nitrogen and/or 1 to 3 sulphur-and/or oxygen atoms, a substituted 5- or 6-membered, saturated,partially saturated or unsaturated heterocycle which may be condensedcontaining 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms byamino, hydroxy, alkoxy, acyloxy, carboxy or mercapto, cycloalkyl orunsubstituted straight chain or branched (C₁₋₂₀)alkyl, (C₁₋₂₀)alkenyl or(C₁₋₂₀)alkinyl, which may be interrupted by N, S and/or O once orseveral times, substituted straight chain or branched (C₁₋₂₀)alkyl,(C₁₋₂₀)alkenyl or (C₁₋₂₀)alkinyl, which may be interrupted by N, Sand/or O, by hydroxy, alkoxy, aryloxy, acyloxy, carbamoyloxy, amino,alkylamino, dialkylamino, trialkylammonium, acylamino, ureido, oximino,imino, carboxy, oxo, halogen, nitro, a carboxylic acid derivative, asulphonic acid derivative, an unsubstituted, 5- or 6-membered,saturated, partially saturated or unsaturated heterocycle containing 1to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms which may becondensed; or a substituted 5- or 6-membered, saturated, partiallysaturated or unsaturated heterocycle which may be condensed containing 1to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atoms by amino,hydroxy, alkoxy, acyloxy, carboxy or mercapto; Z_(p) denotes oxygen orNR_(7p), wherein R_(7p) is as defined R_(2p).

A compound of formula I includes a compound of formula

wherein W and R₅ are as defined above,R_(1p) denotes hydrogen or CH₂F, andR′_(6p) denotes hydrogen, (C₁₋₂₀)alkyl, one or two fold substituted(C₁₋₂₀)alkyl by phenyl, phenoxy, amino, hydroxyphenyl, hydroxy,carboxyl, guanidino or nitroguanidino, unsubstituted phenyl orsubstituted phenyl by acetoxy, pyrrolidinyl; or a compound of formula

A compound of formulae I includes a compound of formulae Ia, Is, I_(p1),I_(p2), and I_(p3) and may be e.g. in free form and in the form of asalt and/or in the form of a solvate. A salt includes any possible salt,e.g. an acid addition salt; such as a hydrochloride, internal salt,metal salt, quaternary salt and an amine salt of a compound of formulaI. Metal salts include for example sodium, potassium, calcium, barium,zinc, aluminum salts, preferably sodium or potassium salts. Amine saltsinclude for example trialkylamine, procaine, dibenzylamine andbenzylamine salts. A salt may preferably be a pharmaceuticallyacceptable salt of a compound of formula I.

A solvate includes a solvate with an organic solvent and a solvate withwater, such as a hydrate. A compound of formula I may be e.g. in theform of a hydrochloride, such as a monohydrochloride, dihydrochloride,trihydrochloride, e.g. in crystalline form and /or in the form of asolvate, e.g. a hydrate. A free form of a compound of formula I may beconverted into a salt form and vice versa. A solvate form of a compoundof formula I, e.g. in free form or in the form of a salt, may beconverted in a non-solvate form and vice versa. A compound of formula Iincludes a compound of formula I in any configuration, e.g. in anypossible steroisomeric form. Mixtures of stereoisomeric forms may beseparated, e.g. as conventional, e.g. by chromatography, fractionedcrystallisation. E.g. the configuration of R₁ in group —C═VR₁ may be syn[(Z)] and anti [(E)] and is preferably, e.g. predominantly, syn [(Z)];e.g. containing the [(E)] form in an amount of 0 to 5%, e.g. 0 to 2%. Acompound of formula I may be in the form of a mixture of the 3(E)-formand 3-(Z)-form, or may be, e.g. predominantly, in the 3(Z)-form, e.g.according to formula

or may be, e.g. predominantly, in the 3(E)-form, e.g. according toformula

wherein R₁ and R₂ are as defined above, and wherein the configuration ofthe group

attached to the nitrogen of the —C═N group in position 3 of the ringsystem is, e.g. 3(E) and/or containing 3(Z). A compound of formula I maybe, e.g. predominantly, in the 3(E)-form, e.g. containing the 3(Z)-formin an amount of 0 to 5%, e.g. 0 to 2% or predominantly in the 3(Z)-form,e.g. containing the 3(Z)-form in an amount of 0 to 5%, e.g. 0 to 2%. Acompound. of formulae Is and I_(p1) may be, e.g. predominantly, in the3(F)-form, e.g. containing the 3(Z)-form in an amount of 0 to 5%, e.g. 0to 2%.

A compound of formula I may be obtained as follows:a) Reacting a compound of formula

wherein W, V and R₁ are as defined above and wherein

-   α) R_(b) denotes hydroxy and R_(c) and R_(d) together denote a bond,    or-   β) R_(d) denotes hydrogen, a cation, an ester moiety or a silyl    group and R_(b) and R_(c) denote the oxo group    e.g. in free form or in the form of an acid addition salt, with a    compound of formula    wherein R₂, R₃ and R₄ are as defined above, e.g. in free form or in    the form of an acid addition salt, e.g. as appropriate, e.g. as    conventional    b) for the production of a compound of formula    wherein W, V, Z. R₁, R₂, R₃, R₅ and R₆ are as defined above,    acylating a compound of formula    wherein Z, R₂, R₃, R₅ and R₆ are as defined above, e.g. in free form    or in the form of an acid addition salt, e.g. as appropriate, e.g.    as conventional with a compound of formula    wherein V, W and R₁ are as defined above and X denotes a leaving    group, e.g. in free form or in the form of an acid addition salt;    e.g. as appropriate, e.g. as conventional; or reacting a compound of    formula    wherein R₁, R₂, R₃, R₅, V and W are as defined above, e.g. in free    form or in the form of an acid addition salt, e.g. as appropriate,    e.g. as conventional with a compound of formula    wherein R₆ and Z are as defined above and X denotes a leaving group.

Reactive groups in a compound of of formulae I, Ib, Ic, II, III, IV, Vand Va may be protected by protecting groups, e.g. protecting groupswhich are conventional, e.g. in cephalosporin chemistry. Silylprotecting group technology in the presence of a solvent which may beinert towards silylation agents, e.g. a chlorinated hydrocarbon, such asdichloromethane; a nitrile such as acetonitrile, an ether such astetrahydrofuran, a dipolar aprotic solvent, e.g. N,N-dimethylformamide;or a solvent system, e.g. mixtures of individual solvents, e.g. asdescribed above; may be appropriate for the protection of reactivegroups. Protecting groups may be split off, e.g. as conventional duringa corresponding reaction or after termination of a correspondingreaction. A compound of formula I wherein R₅ denotes hydrogen may beconverted into a compound of formula I wherein R₅ denotes an estermoiety or vice versa. A compound of formula I may be isolated from thereaction mixture, e.g. as conventional. A compound of formula I may beobtained in free form or in the form of a salt and/or a hydrate. Acompound of formula I in free form may be converted into a compound offormula in the form of a salt and/or a hydrate and vice versa.

Process a) may be carried out as follows:

A compound of formula II may be reacted with a compound of formula III,e.g. in a solvent, e.g. in a solvent which is inert under the reactionconditions, such as water; a mixture of water with an e.g. lower, e.g.(C₁₋₄)alcohol or dioxane; or in a dipolar aprotic solvent, e.g.dimethylformamide, dimethylsulfoxide, dimethylacetamide, if desired inmixture with an alcohol and/or water; at temperatures from −20 to 50° C.The pH may be at an optimum, e.g. by addition of an organic or inorganicacid or base. A compound of formula I obtained may be isolated and/orpurified, e.g. as conventional, e.g. by addition of an anti-solvent orby chromatography.

Process b) may be carried out e.g. as conventional for an acylationreaction. E.g. a compound of formula IV may be reacted with a compoundof formula Va; or a compound of formula Ic may be reacted with acompound of formula Va; e.g. in an appropriate solvent, such as amixture of water and acetone or acetonitrile at appropriatetemperatures, e.g. at room temperature.

Starting compounds are known or may be produced according to known, e.g.analogous methods, or e.g. according to the present examples. A part ofthe starting compounds according to the present invention is novel.

In another aspect the present invention provides a compound selectedfrom

-   1-[(1-Methylhydrazino)iminomethyl]piperazine-   1-[(1-Ethylhydrazino)iminomethyl]piperazine-   1-[(1-Allylhydrazino)iminomethyl]piperazine-   1-[(1-(4-Methoxybenzyl)hydrazino]iminomethyl]piperazine-   1-[(1-(4-Methoxybenzyl)hydrazino]iminomethyl]piperazine-   1-[(1-(3,4,5-Trimethoxybenzyl)hydrazino]iminomethyl]piperazine-   1-[(1-Methylhydrazino)(methylimino)methyl]piperazine-   Glycin-(4-hydrazinoiminomethyl)piperazide-   1-(R)-(Amino(4-hydroxyphenyl)acetyl)4-(hydrazinoiminomethyl)piperazine-   1,4-bis-(Hydrazinoiminomethyl)piperazine-   1-(Hydrazinoiminomethyl)-4-[ethylimino)[3-dimethylan-nopropyl)amino]methyl]piperazine,-   e.g. in the form of a salt, such as a hydrochloride, and/or in the    form of a solvate; and, in another aspect, a compound of formula    wherein R₅ is as defined in claim 1, and R_(int) denotes a group    which is formed by a bond of the terminal amine group of the    hydrazino group of a compound selected from the list above and    wherein the —N— group is substituted according to a compound    selected from the list above, i.e. a hydrazino-compound listed above    is bond to the ring system via the terminal amine group of the    hydrazino group to the methyl group in position 3 of the ring system    to form a group    wherein the —N— group is substituted according to a hydrazino    compound listed above.

The compounds of formulae I, hereinafter designated as “activecompound(s) of the invention” exhibits pharmacological activity andsurprising low toxicity and are therefore useful as pharmaceuticals. Inparticular, the active compounds of the invention show antimicrobial,e.g. antibacterial, activity against aerobic and anaerobic growingbacteria, e.g. gram negative and gram positive bacteria such asEnterobacter, e.g. Enterobacter cloacae; Enterococcus, e.g. Enterococcusfaecalis, Enterococcus faecium; Moraxella, e.g. Moraxella catarrhalis;Haemophilus, e.g. Haemophilus influenza; Klebsiella, e.g. Klebsiellaedwardsii, Klebsiella pneumoniae; Streptococcus, e.g. Streptococcuspyogenes; Staphylococcus, e.g. Staphylococcus aureus MSSA (methicillinsensitive strains); Staphylococcus aureus MRSA (methicillin resistantstrains); Escherichia, e.g. Escherichia coli; Proteus, e.g. Proteusmirabilis, Salmonella, e.g. Salmonella typhimurium, Serratia, e.g.Serratia marcescens, Pseudomonas, e.g. Pseudomonas aeruginosa;Pneumococci, e.g. Pneumococcus pneumoniae (penicillin sensitive andmult-drug resistant strains); in vitro in the Agar DilutionTest forbacteria according to National Commitee for Clinical LaboratoryStandards (NCCLS) 1993,

-   -   Document-M7-A3Vol. 13, No. 25: “Methods for dilution        Antimicrobial Susceptibility Tests for Bacteria that Grow        Aerobically—Third Edition, Approved Standard”; and    -   Document M11-A3 for anaerobic bacteria        in a concentration from about 0.001 to ca. 50 μg/ml (MIC), e.g.        using strains including Staphylococcus aureus (ATCC 29213 and        ATCC 9144); Enterococcus faecalis (ATCC 29212); Haemophilus        influenza (NTCC 49247 and NCRC 11931); Escherichia coli (ATCC        25922 and ATCC 35218); Klebsiella pneumoniae (NCTC 11228);        Klebsiella edwardsii (NCTC 10896); Pseudomonas aeruginosa (ATCC        27853 and ATCC 25668); and in vivo in the septicaemia mouse        model, in accordance to the method description Nr. 159 A-5,        approved by Austrian Health Authorities (MA 58, no.2968/95 of        12, Oct. 1995), e.g. when administered at dosages from about        0.05 to 50 mg/kg body weight, such as 0.1 to 50 mg/kg body        weight (ED₅₀ values). E.g., mice are infected with an ED 95% of        Staphylococcus aureus (ATCC 4995), Streprococcus pyogenes (ATCC        29218), Escherichia coli (Δ 12 NFI culture collection) and are        treated 1, 5 and 24 hours after infection. The ED 50% values        ranging from ca. 0.2 to 50 mg/kg body weight are calculated by        Probit analysis of the administered dosages of compounds.        Activity is determined by numbers of surviving animals per group        of 8 mice per dosage until day 5 after infection. The active        compounds of the invention show an surprising overall activity        spectrum. It has, for example, been determined that the MHK        (μg/ml) of the compound of Example 1 against, for example        Enterococcus faecalis is of ca. 0.1 to 0.4; against        Staphylococcus aureus (MSSA) is of ca. <0.125 to 0.8; against        methicillin resistant Staphyloccous aureus is of 0.8 to 6.4;        against multi-drug resistant Pneumococcus is of 0.4. The active        compounds of the invention are therefore useful for the        treatment of microbial, e.g. bacterial diseases.

For this indication, the appropriate dosage will, of course, varydepending upon, for example, the compound of formula I employed, thehost, the mode of administration and the nature and severity of theconditions being treated. However, in general, for satisfactory resultsin larger mammals, for example humans, an indicated daily dosage is inthe range from about 0.05 to 5 g, for example 0.1 to about 2.5 g, of anactive compound of the invention conveniently administered, for example,in divided doses up to four times a day.

An active compound of the invention may be administered by anyconventional route, for example orally, e.g. in the form of tablets orcapsules, or parenterally in the form of injectable solutions orsuspensions, e.g. in analogous manner to cefotaxime.

The compound7-(((5-amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluormethoxyimino)acetyl)amino)-3-((imino-1-piperazinylmethyl)methylhydrazono)methyl-3-cephem4-carboxylicacid (compound of Example 1) is the preferred compound of the inventionfor use as an antimicrobial agent. It has, for example been determinedthat the MHK (μg/ml) of the compound of Example 1 (tested in the form ofthe hydrochloride) against, for example Haemophilus influenza is ca.<0.125 to 0.4 and, for example cefotaxime shows an MHK (μg/ml) of ca.<0.125 to 0.4. It is therefore, indicated that for the treatment ofmicrobial diseases, e.g. bacterial diseases the preferred compounds ofthe invention may be administered to larger mammals, for example humans,by similar modes of administration at similar dosages thanconventionally employed with cefotaxime.

A compound of formula I may be administered in the form of apharmaceutically acceptable salt, e.g. an acid addition salt or a baseaddition salt or in the corresponding free form, if desired in the formof a solvate. Such a salt/solvate may exhibit the same order of activityas the free form.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula I according to claim 1 in the form of apharmaceutically acceptable salt or in free form in association with atleast one pharmaceutical carrier or diluent.

Such compositions may be manufactured in conventional manner. Unitdosage form may contain, for example 10 mg to about 1 g, for example 10mg to about 700 mg, such as to about 500 mg.

As medicaments, the active ingredients according to the invention may beadministered alone or in suitable medicinal forms together withinorganic or organic, pharmacologically inert excipients. For example,they are used as a constituent of capsules, or injection or instillationpreparations, which contain a quantity of active compounds that issufficient to attain an optimum blood level, that is, ca. 10 to 500 mgper capsule. For this application, the dosage to be administered dependson the compound used and the type of administration, as well as the typeof treatment. With larger mammals, satisfactory results may be obtainedwhen administering a daily dose of ca. 0.5 to 6 g. If required, thisamount may be given in correspondingly smaller doses two to four timesdaily, or in sustained release form.

In another aspect the present invention provides a compound of formula Ior a composition comprising a compound of formula I in the form of apharmaceutically acceptable salt or in free form in association with atleast one pharmaceutical carrier or diluent for use as a pharmaceutical,e.g. as an antibiotic; and The use of a compound of formula I, or use ofa composition comprising a compound of formula I in the form of apharmaceutically acceptable salt or in free form in association with atleast one pharmaceutical carrier or diluent as a pharmaceutical.

In a further aspect the present invention provides a method of treatmentof microbial diseases, e.g. caused by bacterias selected fromPseudomonas, Enterobacter, Enterococcus, Moraxelia, Haemophilus,Klebsiella, Streptococcus, Staphylococcus, Escherichia, Proteus,Salmonella, Serratia or Pneumococci, which comprises administering to asubject in need of such treatment, an effective amount of a compound offormula I; e.g. in the form of a pharmaceutical composition according tothe present invention; and A compound of formula I for use in thepreparation of a medicament for the treatment of microbial diseases, forexample of diseases caused by bacterias selected from Pseudomonas,Enterobacter, Enterococcus, Moraxella, Haemophilus, Klebsiella,Streptococcus, Staphylococcus, Escherichia, Proteus, Salmonella,Serratia or Pneumococci.

In the following examples, which illustrate the invention more fully butshould in no way limit its scope, all temperatures are given in degreesCelsius. ¹H-NMR: 200 MHz, DMSO-d₆.

EXAMPLE 17-(((5-amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluormethoxyimino)acetyl)amino)-3-(imino-1-piperazinylmethyl)methylhydrazono)methyl-3-cephem-4-carboxylicacid a)N-(1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto(2,1-b)furo(3,4-d)(1,3)-thiazin-6-yl)-2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-(fluoromethoxyimino)aceticacid amide (hydroxylactone of7-(((5-amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluoromethoxyimino)acetyl)amino)-3-formyl-3-cephem-4-carboxylic acid)

A suspension of 10 g of 7-amino-3-formyl-3-cephem4-carboxylic acid in amixture of 220 ml of methylene chloride and 80 ml of acetonitrile isstirred at 0° with 43 ml of N,O-bis(trimethylsilyl)-acetamide. 15.7 g of(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyimino-acetic acidchloride are added to the clear solution obtained and the reactionmixture is stirred for ca. one hour at ca. 0°. The mixture is dilutedwith 1250 ml of acetonitrile which contains 70 ml of water. 12% aqueousammonia is added to the mixture obtained to adjust a pH value of 3.5.The mixture is diluted with 2.5 litres of water and extracted with ethylacetate. The ethyl acetate phase is dried and concentrated. Theconcentrate is stirred for one hour at 20° with 100 ml of acetonitrile.N-(1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto(2,1-b)furo(3,4-d)(1,3)-thiazin-6-yl)-2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-(fluoromethoxyimino)aceticacid amide precipitates in crystalline form, is filtrated off and dried.

b)7-(((5-amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluoromethoxyimino)acetyl)amino)-3(E)-(imino-1-piperazinylmethyl)methylhydrazono)methyl-3-cephem-4-carboxylicacid

3.77 g ofN-(1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto(2,1-b)furo(3,4-d)(1,3)-thiazin-6-yl)-2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyimino)aceticacid amide are suspended in a mixture of 75 ml of acetonitrile and 11 mlof water and treated with a solution of 2 g of1-(1-methylhydrazino)iminomethyl)piperazine in the form of adihydro-chloride in 4.5 ml of 2N HCl. The reaction mixture is stirredfor ca. one day at room temperature and poured into 600 ml ofacetonitrile under stirring.7-(((5-amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluoromethoxy-imino)acetyl)amino)-3(E)-(imino-1-piperazinylmethyl)-methylhydrazono)methyl-3-cephem-4-carboxylicacid in the form of a trihydrochloride precipitates, is filtrated off,washed with acetonitrile and dried.

c)7-(((5-amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluoromethoxyimino)acetyl)amino)-3(E)-(imino-1-piperazinylmethyl)methylhydrazono)methyl-3-cephem-4-carboxylicacid

0.65 g of crude7-(((5-amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluoromethoxy-imino)acetyl)amino)-3(E)-(imino-1-piperazinylmethyl)methylhydrazono)methyl-3-cephem-4-carboxylicacid in the form of a trihydrochloride obtained in step b) are dissolvedin 2 ml of water and filled into a column which is filled with 50 g ofRP-18^(R) (LiChroprep RP-18^(R), grain size 40-63 μm, Merck) and eluatedwith water (flow rate 20 ml/min). Fractions are examined by means ofanalytical HPLC and the fractions which contain7-(((5-amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluorometh-oxyimino)acetyl)-amino)-3(E)-(imino-1-piperazinylmethyl)methylhydrazono)methyl-3-cephem-4-carboxylicacid in the form of a monohydrochlorid are determined (HPLC), combinedand lyophilised.

In the manner described in Example 1 but using corresponding compoundsof formulae II and III wherein W, V, R₁, R₂, R₃, R₄ and R₅ have themeaning given in TABLE 1 below, compounds of formula I, wherein W═N,V═N—O, R₄═R₅═H and R₁═CH₂F and R₂ and R₃ have the meaning listed inTABLE 1 below are obtained, e.g. in the salt form described: TABLE 1 Ex.R₂ R₃ Salt 2 C₂H₅ H HCl 3 CH₃ C₂H₅ HCl 4 —CH₂CH═CH₂ H 3HCl 5 CH₃ CH₃ HCl6

H 3HCl 7

H 3HCl

EXAMPLE 86R-(6a,7β(Z)-7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-[[(imino4-(ethoxycarbonyl)piperazin-1-ylmethyl)hydrazono]methyl]-3-cephem-4-carboxylicacid

5.2 g of N,O-bistrimethylsilyl acetamide are added dropwise whilststirring to a suspension of 1 g of6R-(6a,7b(Z))-7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl-amino]-3-[[(imino-1-piperazinylmethyl)hydrazono]methyl]-3-cephem4-carboxylicacid in the form of a trihydrochloride in a mixture of 50 ml of absolutemethylene chloride and 50 ml of absolute acetonitrile. To the clearsolution obtained 0.28 g of chloroformic acid ethyl ester are addeddropwise whilst stirring. The mixture is stirred for ca. 20 minutes atroom temperature and treated with 0.95 g of water.6R-(6a,7b(Z))-7-[2-(2-aminothiazol-4yl)-2-hydroxyiminoacetyl-amino]-3-[[(imino4-(ethoxycarbonyl)piperazin-1-ylmethyl)hydrazono]methyl]-3-cephem4-carboxylicacid in the form of a dihydrochloride precipitates, is filtrated off,washed and dried.

EXAMPLE 96R-(6a,7β(Z))-7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-[[(imino--4(aminoacetyl)piperazin-1-ylmethyl)hydrazono]methyl]-3-cephem-4-carboxylicacid

0.6 g of glycine-(4-hydrazinoiminomethyl)piperazide in the form of adihydrochloride are added in one portion to a solution of 0.6 g ofN-(1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazin-6-yl)-2-(2-aminothiazol4-yl)-(Z)-2-(hydroxy-imino)aceticacid amide in a mixture of 10.7 ml of acetonitrile, 3.6 ml of water and0.7 ml of 8 N HCl, and the reaction mixture obtained is stirred at roomtemperature.6R-(6a,7β(Z))-7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-[[(imino-4-(aminoacetyl)piperazin-1-ylmethyl)hydrazono]methyl]-3-cephem4-carboxylicacid in the form of a trihydrochloride precipitates within 2 hourswhilst stirring, is filtrated off, washed and dried.

In the manner as described in Examples 8 and 9 but using correspondingcompounds of formulae II and III wherein W, V, R₁, R₂, R₃, R₄ and R₅have the meaning given in TABLE 2 below, compounds of formula I, whereinV═N—O, R₂═R₃═R₅═H and W, R₁ and R₄ have the meaning listed in TABLE 1below are obtained, e.g. in the salt form described: TABLE 2 Example WR₁ R₄ Salt 10 CH H

2HCl 11 CH H —COCH₃ 2HCl 12 CH H

2HCl 13 CH H

3HCl 14 CH H —CO—N(CH₃)₂ 2HCl 15 CH H

2HCl 16 CH H

3HCl 17 CH H

2HCl 18 CH H

3HCl 19 CH H

3HCl 20 CH H

3HCl 21 CH H —CO—CH₂OH 2HCl 22 CH H

4HCl 23 CH H

2HCl 24 CH H

3HCl 25 CH H —CO—(CH₂)₅—CH₃ 2HCl 26 CH H —CO—(CH₂)₁₆—CH₃ 2HCl 27 CH H—CO—(CH₂)₁₄—CH₃ 2HCl 28 CH H —CO—(CH₂)₆—CH₃ 2HCl 29 CH H

2HCl 30 N CH₂—F

2HCl 31 N CH₂—F

2HCl 32 N CH₂—F —CO—CH₃ 2HCl 33 N CH₂—F

3HCl 34 N CH₂—F —CO—CH₂—NH₂ 3HCl 35 N CH₂—F

3HCl 36 N CH₂—F

3HCl 37 N CH₂—F

3HCl 38 N CH₂—F

3HCl 39 CH H

3HCl 40 CH H —CO—(CH₂)₂—COOH 2HCl 41 CH H

2HCl 42 CH H

2HCl 43 N CH₂—F

2HCl 44 CH H

3HCl 45 CH H

3HCl

EXAMPLE 46[6(R)-6a,7β(Z)]-7-[[(5-amino-1,2,4-thiadiazol-3-yl)-(fluoromethoxyimino)-acetyl)]amino]3-[(imino-4-acetylpiperazin-1-ylmethyl)hydrazonomethyl]-3-cephem-4-carboxylicacid-1-(isopropoxycarbonyloxy)ethylester

1.5 g of[6(R)-6a,70β(Z)]-7-[[(5-amino-1,2,4-thiadiazol-3-yl)-(fluoromethoxyimino)acetyl]-amino]-3-[(iminopiperazine-1-ylmethyl)hydrazonomethyl]-3-cephem-4-carboxylicacid-1-(iso-propoxycarbonyloxy)ethylester in the form of adihydrochloride are stirred at 0° in a mixture of 30 ml of methylenechloride, 10 ml of acetonitrile and 15 ml of dimethylformamide with 2.2ml of N,O-bistrimethylsilyl acetamide. To the clear solution obtained160 ml of acetyl chloride are added, stirring is continued for ca. 60minutes at 0°. The reaction mixture is introduced into 100 ml of water.The pH of the mixture obtained is adjusted to 7 by addition of 0.5 Nsodium bicarbonate solution and the mixture obtained is extracted withethyl acetate. The ethyl acetate phase is washed with water, dried oversodium sulphate and the solvent is evaporated off. The residue istreated with ether.[6(R)-6a,7β(Z)]-7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-(fluoromethoxyimino)-acetyl]amino]3-[(imino-4-acetylpiperazin-1-ylmethyl)hydrazonomethyl]-3-cephem-4-carboxylicacid-1-(isopropoxycarbonyloxy)ethylester (mixture of twodiastereoisomers in a ration of 1:1) precipitates, is filtrated off anddried.

EXAMPLE 47[6(R)-6α,7β(Z)]-7-[[(5-Amnino-1,2,4-thiadiazol-3-yl)-(fluormethoxyimino)acetyl]amino]-3-[(iminopiperazin-1-ylmethyl)hydrazonomethyl]-3-cephem-4-carboxylicacid-1-(isopropoxycarbonyloxy) ethylester

3.1 g of [6(R)-6α,7β(Z))-7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-(fluormethoxyimino)acetyl]-amino]-3-formyl-3-cephem-4-carboxylicacid-1-(isopropoxycarbonyloxy)ethylester in 30 ml of acetonitrile aretreated with a solution of 1.11 g of 1-(hydrazinoimino-methyl)piperazinein the form of a dihydrochloride in 2.5 ml of 2 N hydrochloric acid. Themixture is stirred for ca. 1 hour and introduced into 300 ml ofacetonitrile.[6(R)-6α,7β(Z)]-7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-(fluormethoxyimino)acetyl]amino]-3-[(iminopiperazin-1-ylmethyl)hydrazonomethyl]-3-cephem-4-carboxylicacid-1-(isopropoxycarbonyloxy)ethylester in the form of adihydrochloride (mixture of two diastereoisomers in a ration of 1:1)precipitates, is filtrated off, washed and dried.

In the manner described in Example 47 but using corresponding startingcompounds of formulae II and III wherein W, V, R₁, R₂, R₃, R₄ and R₅have the meaning given in TABLE 3 below, compounds of formula I, whereinW═N, V═N—O, R₁═CH₂F, R₂═R₃═H and R₄ and R₅ are as listed in TABLE 3below are obtained: TABLE 3 Ex- ample R₄ R₅ 48

49

—CH₂—OCOC(CH₃)₃ 50 H —CH₂—OCOC(CH₃)₃

Compounds useful as starting material according to the present inventionmay e.g. be produced as follows:

EXAMPLE A 1-(1-Methylhydrazino)iminomethyl)piperazine a)S-Methyl-2-methyl-isothiosemicarbazide

A solution of 239.8 g of S-methyl-2-methylisothio-semicarbazide in theform of a hydriodide in 100 ml of water is placed on a column filledwith 1500 ml of a strong basic ion exchanger in chloride form (AmberliteIRA 420^(R)), and eluted with water. The fractions containingS-methyl-2-methylisothio-semi-carbazide in the form of a hydrochloride(HPLC) are lyophilised. The lyophilisate is treated with ether, isolatedby filtration and dried. S-methyl-2-methyl-isothiosemicarbazide in theform of a hydrochloride is obtained in the form of a white solid.

M.p.: 116° (isopropanol).

b) Benzylidene derivative of4-formyl-1-((1-methylhydrazino)imino-methyl)piperazine

A solution of 40.9 g of S-methyl-2-methyl-isothiosemicarbazide in theform of a hydrochloride in 350 ml of ethanol is mixed with 30 g offreshly distilled formylpiperazine and heated under reflux for ca. 39hours. The reaction mixture is cooled to room temperature, mixed with26.4 ml of benzaldehyde and stirred for ca. 24 hours. The precipitateobtained is filtrated off, washed with ethanol and dried. Thebenzylidene derivative of4-formyl-1-((1-methyl-hydrazino)imino-methyl)piperazine in the form of ahydrochloride is obtained.

c) 1-((1-Methylhydrazino)iminomethyl)piperazine

From 10 g of the benzylidene derivative of4-formyl-1-((1-methylhydrazino)iminomethyl)piperazine in the form of ahydrochloride the benaldehyde is split off by steam distillation underaddition of 48 ml of 2N HCl. The aqueous slurry obtained is concentratedand an oily residue is obtained which is treated with boiling ethanol.The ethanolic phase is concentrated in vacuum.1-((1-Methylhydrazino)iminomethyl)piperazine in the form of adihydrochloride is obtained in the form of a white solid.

EXAMPLE B 1-[(1-Ethylhydrazino)iminomethyl]piperazine a) Benzylidenederivative of 1-(hydrazinoiminomethyl)piperazine

The pH of a solution of 10.7 g of the benzylidene derivative of1-(hydrazinoiminomethyl)piperazine in the form of a dihydrochloride in100 ml of water is adjusted to 10 by addition of 8N NaOH. The mixtureobtained is extracted with ethyl acetate. The ethyl acetate phase isdried and the solvent is evaporated off. The benzylidene derivative of1-(hydrazinoiminomethyl)piperazine is obtained in the form of anamorphous powder.

b) Benzylidene derivative of 1-formyl-4-(hydrazinoiminomethyl)piperazine

12.7 ml of acetic acid anhydride are added dropwise to 42 ml ofice-cooled formic acid, the mixture is stirred for ca. 1 hour and 16 gof the benzylidene derivative of 1-(hydrazinoiminomethyl)piperazine in42 ml of formic acid are added dropwise. The mixture is left for ca. 2hours at 0° and the solvent is evaporated off. The residue is treatedwith water and the pH of the mixture obtained is adjusted to pH 11 byaddition of 10N KOH. The mixture is extracted with dichloromethane, thedichloromethane phase is dried and the solvent is evaporated off. Thebenzylidene derivative of 1-formyl4-(hydrazinoiminomethyl)piperazine isobtained in the form of a white powder.

c) Benzylidene derivative of1-[(1-ethylhydrazino)iminomethyl]4-formylpiperazine

An ice-cooled solution of 2 g of the benzylidene derivative of1-formyl4-(hydrazinoiminomethyl)piperazine in 40 ml of drytetrahydrofurane is treated with 9.3 ml ofbis-(trimethyl-silyl)-lithiumamid (1M solution in tetrahydrofurane) andstirred for ca. 1 hour at 0°. 2.4 g of ethyl iodide are added to thereaction mixture and the mixture is stirred overnight at roomtemperature. The solvent is evaporated off and the residue is purifiedvia “Dry-column-flash-chromatography”: Eluent: 1. methanol; 2. 90%methanol/10% acetic acid.

Fractions containing the benzylidene derivative of1-[(1-ethylhydrazino)iminomethyl]4-formylpiperazine (analytical HPLCdetermination) are combined, the solvent is evaporated off and thebenzylidene derivative of1-[(1-ethylhydrazino)iminomethyl]4-formylpiperazine is obtained in theform of a white powder.

d) 1-[(1-Ethylhydrazino)iminomethyl]piperazine

2.7 g of the benzylidene derivative of1-[(1-ethylhydrazino)iminomethyl]4-formylpiperazine dissolved in 11.6 mlof 2N HCl are treated by steam distillation. After evaporation of thewater from the mixture obtained and drying of the residue1-[(1-ethylhydrazino)iminomethyl]piperazine in the form of adihydrochloride is obtained in the form of a white solid.

In the manner as described in Example B, but using the correspondingreactants the following compounds may be obtained:

EXAMPLE C 1-[(1-Allylhydrazino)iminomethyl]piperazine (in the form of adihydrochloride) EXAMPLE D1-[[1-(4-Methoxybenzyl)hydrazino]iminomethyl]piperazine (in the form ofa dihydrochloride) EXAMPLE E1-[[1-(3,4,5-Trimethoxybenzyl)hydrazino]iminomethyl]piperazine (in theform of a dihydrochloride) EXAMPLE F 1-[(1-Methylhydrazino)(methylimino)methyl]piperazine a) Benzylidenederivative of 1-formyl-4-[hydrazino(methylimino)methyl]piperazine

37 g of 1-formyl4-[hydrazino(methylimino)methyl]piperazine in the formof a hydrochloride dissolved in a mixture of 80 ml of acetonitrile and185 ml of water are treated with 30 g of benzaldehyde. The mixture isstirred for ca. 3 hours at room temperature and extracted with ether.The water of the aqueous phase is evaporated. The residue is treatedwith water and a pH of 11 of the mixture is adjusted with 2N NaOH. Themixture is extracted with dichloromethane, the organic phase is dried,the solvent evaporated and the residue is dried. The benzylidenederivative of 1-formyl4-[hydrazino(methylimino)methyl]piperazine isobtained in the form of a white powder.

b) Benzylidene derivative of1-formyl-4-[(1-methylhydrazino)(methylimino)methyl]piperazine

A solution of 1,62 g of the benzylidene derivative of1-formyl-4-[hydrazino(methylimino)methyl]piperazine in 30 ml ofacetonitrile is treated with 4,56 g of methyl iodide and the mixture isrefluxed overnight. The solvent is evaporated off and the residue isstirred with 20 ml of water and 10 ml Amberlite IRA-400 (Cl)^(R) (ionexchange resin) for ca. 1 hour at room temperature. The mixture isfiltrated. The aqueous solution is adjusted to a pH of 11 with 2N NaOHand extracted with dichloromethane. The organic phase is dried andconcentrated by solvent evaporation. For purification the concentrate istreated in the manner as described in Example B, c). The benzylidenederivative of1-formyl4-[(1-methylhydrazino)(methylimino)methyl]piperazine is obtainedin the form of a white powder.

c) 1-[(1-Methylhydrazino)(methylimino)methyl]piperazine

1.14 g of the benzylidene derivative of1-formyl4-[(1-methylhydrazino)(methylimino)methyl]piperazine dissolvedin 6 ml of 2N HCl are treated in the manner as described in Example Bd).1-[(1-Methylhydrazino)(methylimino)methyl]piperazine in the form of adihydrochloride is obtained in the form of a white solid.

EXAMPLE G

In the manner as described in Example F but using the correspondingreactants 1-[(1-methylhydrazino)(ethylimino)methyl]piperazine (in theform of a dihydrochloride) is obtained.

EXAMPLE H Glycine-(4-hydrazinoiminomethyl)piperazide a) Benzylidenederivative of 1-(hydrazinoiminomethyl)piperazine

15 g of 1-(hydrazinoiminomethyl)piperazine in the form of adihydrochloride in a mixture of 50 ml of methanol and 50 ml of water aretreated with 12 g of benzaldehyde. The mixture is stirred for ca. 1 hourat room temperature and extracted with ether. The aqueous phase isevaporated off and the residue is treated with absolute methanol. Thesolvent is evaporated off and the benzylidene derivative of1-(hydrazinoiminomethyl)piperazine in the form of a dihydrochloride isobtained in form of a colourless powder.

b) Benzylidene derivative ofN-benzyloxycarbonylglycin-(4-hydrazinoiminomethyl)piperazide

2 g of benzyloxycarbonyl-glycine-N-succinimidylester in 50 ml ofabsolute methylenchloride are treated with 2 g of triethylamine and with2 g of the benzylidene derivative of 1-(hydrazinoiminomethyl)piperazinein the form of a dihydrochloride. The mixture is stirred for ca. 20minutes at room temperature. The benzylidene derivative ofN-benzyloxycarbonylglycin-(4-hydrazinoiminomethyl)piperazideprecipitates, is filtrated off and dried.

c) Glycine-(4-hydrazinoiminomethyl)piperazide

A mixture of 2.3 g ofN-benzyloxycarbonylglycin-(4-hydrazinoiminomethyl)piperazide, 60 ml ofethanol, 5.5 ml of 2 N HCl and 1.2 g of 10% palladium on charcoal aretreated with hydrogen in an autoclave under stirring at roomtemperature. After ca. 12 hours the mixture is filtrated and the solventin the filtrate is evaporated off. The residue is treated with ethanoland ethanol is evaporated off.Glycine-(4-hydrazinoiminomethyl)piperazide in the form of adihydrochloride is obtained in form of a white powder.

EXAMPLE I 1,4-bis-(Hydrazinoiminomethyl)piperazine a)1,4-bis-Thiocarbamoylpiperazine

4.4 g of 1,4-dicyanopiperazine in a solution of 3.5 g hydrogen sulfideand 1.5 g of triethylamine in 150 ml of ethanol are heated in anautoclave at 110° for ca. 3 hours and the mixture is cooled to roomtemperature. 1,4-bis-thiocarbamoylpiperazine in the form of adihydrochloride precipitates, is filtrated off and dried.

b) 1,4-Bis-[imino(methylthio)methyl]piperazine

5.5 g of 1,4-bis-thiocarbamoylpiperazine in 150 ml of methanol artreated with 15 g of methyliodide. The mixture obtained is heated underreflux for ca. 5 hours and stirred for ca. 43 hours at room temperature.A precipitate of 1,4-bis-[imino(methylthio)-methyl]-piperazine in theform of a dihydroiodide is obtained, filtrated off, washed withmethanol, dried, dissolved in water and treated with a strong basic ionexchange resin in the chloride form under stirring for ca. 24 hours. Theion exchange resin is filtrated off and the filtrate is lyophilised.1,4-bis-[imino(methyl-thio)methyl]piperazine in the form of adihydrochloride is obtained.

c) 1,4-Bis-(hydrazinoiminomethyl)piperazine

4.2 g of 1,4-bis-[imino(methyl-thio)methyl]piperazine in the form of adihydrochloride in 60 ml of water are treated with 1.45 g of hydrazinehydrate. The mixture is stirred for ca.15 hours at room temperature andthe solvent is evaporated off. The residue is dissolved in 15 ml of hotwater. 400 ml of ethanol are added to the solution obtained and themixture is stirred at room temperature and at 0°.1,4-Bis-(hydrazinoiminomethyl)piperazine in the form of adihydrochloride precipitates, is filtrated off and dried.

EXAMPLE J1-(Hydrazinoiminomethyl)4-[(ethylimino)[(3-dimethylaminopropyl)amino]methyl]piperazinea) Benzylidene derivative of 1 -(hydrazinoiminomethyl)piperazine

The pH of a m mixture of 10.7 g of the benzylidene derivative of1-(hydrazinoiminomethyl)piperazine in the form of a dihydrochloride(obtained according to Example H, a)) in 100 ml of water is adjusted to10 with 8 N NaOH. The mixture is extracted with ethyl acetate. The ethylacetate phase is dried over Na₂SO₄ and the solvent is evaporated off.The benzylidene derivative of 1-(hydrazinoiminomethyl)piperazine isobtained in form of a powder.

b) Benzylidene derivative of1-(hydrazinoiminomethyl)-4-[(ethyl-imino)[(3-dimethylaminopropyl)amino]methyl]piperazine

1 g of 1-(hydrazinoiminomethyl)piperazine in 5 ml of dimethylformamideare treated with 828 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidin the form of a hydrochloride and stirred for ca. 1 week at roomtemperature. The mixture is introduced into 100 ml of ether. An oilprecipitates. The oil obtained is dissolved in acetonitrile and thesolution obtained is treated with 8.6 ml of 1N etheric hydrochloricacid. The benzylidene derivative of1-(hydrazinoiminomethyl)-4-[(ethyl-imino)[(3-dimethylaminopropyl)amino]methyl]piperazinein the form of a trihydrochloride crystallizes, is filtrated off anddried.

c)1-(Hydrazinoiminomethyl)-4-[(ethylimino)[(3-dimethylaminopropyl)amino]methyl]piperazine

1.4 g of the benzylidene derivative of1-(hydrazinoiminomethyl)-4-[(ethyl-imino)[(3-dimethylaminopropyl)amino]methyl]piperazinein the form of a trihydrochloride are heated in 20 ml of water anddistilled under addition of water until no further benzaldehyde isdistilled off. The water in the destination residue is evaporated offand the residue is treated with isopropanol and the isopropanol isdistilled off (3 times).1-(Hydrazinoiminomethyl)-4-[(ethylimino)[(3-dimethylaminopropyl)amino]methyl]piperazinsin the form of a trihydrochloride is obtained in the form of a whitesolid.

EXAMPLE L[6(R)-6α,7β(Z)]-7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-(fluormethoxyimino)acetyl]amino]-3-formyl-3-cephem-4-carboxylicacid-1-(isopropoxycarbonyloxy)ethylester a)[6(R)-6α,7β(Z)]-7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-(fluormethoxy-imino)acetyl]amino]-3-formyl-3-cephem-4-carboxylicacid

0.4 ml of Hünig-base are added dropwise to 1 g ofN-(1,4,5a,6-Tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin-6-yl)-2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-(fluormethoxyimino)aceticacid amide in 76 ml of acetonitrile. The solution obtained is treatedwith 0.38 g of sodium iodide dissoluted in 5 ml of acetonitrile.[6(R)-6α,7β(Z)]-7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-(fluormethoxy-imino)acetyl]amino]-3-formyl-3-cephem-4-carboxylicacid in the form of a sodium salt precipitates, is filtrated off anddried.

b)[6(R)-6α,7β(Z))-7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-fluormethoxyimino)acetyl]amino]-3-formyl-3-cephem-4-carboxyylicacid-1-(isopropoxycarbonyloxy)ethylester

1 g of[6(R)-6α,7β(Z)]-7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-(fluormethoxy-imino)acetyl]amino]-3-formyl-3-cephem-4-carboxylicacid in the form of a sodium salt in 10 ml of dimethyl-acetamide istreated at 0° under stirring with a solution of 0,65 g of1-iodoethylisopropylcar-bonate in 4 ml of toluene and the mixtureobtained is stirred for ca. 90 minutes at 0°. The mixture obtained isdiluted with 100 ml of ethyl acetate and extracted with an aqueouspotassium hydrogencarbonate solution. The organic phase is extractedwith water, dried over NA₂SO₄ and concentrated to a volume of 10 ml. Theconcentrate obtained is introduced into 120 ml of n-hexane. A mixture oftwo diastereoisomers in a ratio of ca. 1:1 of[6(R)-6α,7β(Z))-7-[[(5-Amino-1,2,4-thiadiazol-3-yl)-fluormethoxyimino)-acetyl]amino]-3-formyl-3-cephem-4-carboxyylicacid-1-(isopropoxycarbonyloxy)ethylester precipitates, is filtrated off,dried and obtained in form of a solid.

EXAMPLE K1-(R-(Amino(4-hydroxyphenyl)acetyl)4-(hydrazinoiminomethyl)piperazine a)Benzylidene derivative of1-(R)-(amino(4-hydroxyphenyl)acetyl)4-(hydrazinoiminomethyl)piperazine

4.85 g(R)-4-Hydroxy-α-[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]-phenylaceticacid in the form of a potassium salt in 30 ml methylene chloride aretreated under stirring with 1.28 g of dimethylacetamide and 1 drop of3-picoline. The mixture obtained is cooled to ca. −30°, treated with 2 gof pivaloylchloride in 10 ml of methylene chloride and stirred for ca.35 minutes at ca. −12°. The mixture obtained is cooled to −40° andtreated with a mixture which is cooled to 0° of 5 g of the benzylidenederivative of 1-(hydrazinoiminomethyl)piperazine in the form of adihydrochloride and 3.4 g of triethylamine in 30 ml of methylenechloride. The mixture obtained is stirred for ca. 20 minutes at ca. −30°and for ca. 20 minutes at −10°, treated at 0° with a mixture of 75 ml ofwater, 10 ml conc. HCl and 6 ml of methylene chloride, stirred for ca.20 minutes at 0° and warmed to room temperature. A two-phase mixture isobtained. The phases are separated and the pH of the aqueous phase isadjusted to 8.0 with triethylamine. The benzylidene derivative of1-(R)-(amino(4-hydroxyphenyl)acetyl)4-(hydrazinoimino-methyl)piperazineprecipitates, is filtrated off, dried and obtained in the form of awhite solid.

b)1-(R)-(Amino(4-hydroxyphenyl)acetyl)4-(hydrazinoimino-ethyl)piperazine

A mixture of 0.3 g of the benzylidene derivative of1-(R)-(amino(4-hydroxyphenyl)acetyl)4-(hydrazino-imino-methyl)piperazine,60 ml of ethanol, 1 ml of 2N HCl and 0.1 g of 10% palladium on charcoalare treated with hydrogen in an autoclave under stirring overnight atroom temperature. The mixture obtained is filtrated and the filtrate isconcentrated in vacuo. The concentrate obtained is treated with 50 ml ofethanol and the solvent is evaporated off.1-(R)-(Amino(4-hydroxyphenyl)acetyl)4-(hydrazinoiminoethyl)piperazine inthe form of a trihydrochloride is obtained in the form of a white solid.

¹H-NMR-Spectra

Ex.

1: 3,25 (broad, 4H, —CH₂—N—CH₂—); 3,3 (s, 3H, N—CH₃); 3,60 and 4,28 (ABquartet, J=18 Hz, 2H, SCH₂); 3,74 (broad, 4H, —CH₂—NH⁺—CH₂—); 5,28 (d,J=5 Hz, 1H, β-lactam-H); 5,78 (d, J=55 Hz, 2H, CH₂F); 5,91 (dd, J=5 and8,3 Hz, 1H, β-lactam-H); 8,1 (s 1H, CH═N); 9,04 (broad singulet, 1H,NH); 9,35 (broad singulet, 1H, NH); (9,81 (d, J=8,3 Hz, 1H, NH), 9,9(broad singulet, 2H, NH₂).

2: 1.17, t, J=5 Hz, 3H, CH₃; 3.28, b, 4H, N—CH₂; 3.60 and 4.21,AB-quartet, J=18 Hz, 2H, S—CH₂; 3.67, b, 4H, N—CH₂, 3.91, m, 2H, CH₂;5.22, d, J=5 Hz, 1H, β-lactam-H, 5.82, d, J=55 Hz, 2H, CH₂F; 5.85, dd,J=5 Hz and 8 Hz, 1H, β-lactam-H; 8.35, b, 3H, 1H CH═N and 2H, NH; 9.78,d, J=8 Hz, 1H, NH.

3: 1.18, t, J=5 Hz, 3H, CH₃; 3.30, b, 9H, 4H of NCH₂ and 2H of CH₂ and3H of CH₃; 3.70, m, 5H, 4H of NCH₂ and 1H of S—CH₂; 4.10, part ofAB-quartet, J=18 Hz, 1H, SCH₂; 5.32, d, J=5 Hz, 1H, β-lactam-H; 5.82, d,J=55 Hz, 2H, CH₂F; 5.95, dd, J=5 Hz and 8 Hz, 1H, β-lactam-H; 8.08, s,1H, CH═N; 8.32, b, 1H, NH; 9.82, d, J=8 Hz, 1H, NH.

4: 3.30, b, 4H, N—CH₂; 3.58 and 4.25, AB-quartet, J=18 Hz, 2H, S—CH₂;3.73, b, 4H, N—CH₂; 4.30, m, 2H, N—CH₂; 5.26, m, 3H, 1H β-lactam-H and2H of CH₂═C; 5.64, part of dublet, 1H, CH₂F; 5.90, m, 4H, 1H of CH₂—Fand 1H of CH═C adn 1H β-lactam-H; 8.11, s, 1H, CH═N; 9.81, d, J=8 Hz,1H, NH.

5: 90 and 03, 2s (2:1), 3H, N-3-CH₃; 3.33, b, 7H, 4H of —CH₂ and H₃,3.64, b, 5H, 4H of NH₂ and 1H of S—CH₂; 4.15, part of AB-quartet; J=18Hz, 1H, S—CH₂; 5.21, d, J=5 Hz, 1H, β-lactam-H; 5.81, d, J=55 Hz, 2H,CH₂F; 5.83, dd, J=5 Hz and J=8 Hz, 1H, β-lactam-H; 8.32, 3H, 1H of CH═Nand 2H of NH; 9.79, d, J=8 Hz, 1H, NH.

6: 3.31, b, 4H, N—CH₂; 3.52 and 4.18, AB-quartet, J=18 Hz, 2H, S—CH₂,3.72, b, 7H, 4H of N—CH₂ and 3H of OCH₃; 4.95, AB-quartet, J=17 Hz, 2H,CH₂; 5.14, d, J=5 Hz, 1H, β-lactam-H; 5.78, d, J=55 Hz, 2H, CH₂F; 5.77,dd, J=5 Hz and 8 Hz, 1H, β-lactam-H; 6.86-6.91, m, 2H, CH-arom.;7.15-7.19, m, 2H, CH-arom.; 8.26, b, 2H, CH═N and NH; 8.40, b, 1H, NH;9.74, d, J=8 Hz; 1H, NH.

7: 3.34, b, 4H, N—CH₂; 3.57 and 4.23, AB-quartet, J=18 Hz, 2H, S—CH₂;3.64, s, 3H, OCH₃; 3.79, b, 10H, 4H of N—CH₂ and 6H of OCH₃; 5.03,AB-quartet, J=17 Hz, 2H, CH₂; 5.27, d, J=5 Hz, 1H, β-lactam-H; 5.81, d,J=55 Hz, 2H, CH₂F; 5.92, dd, J=5 Hz and 8 Hz, 1H, β-lactam-H; 6.53, s,2H, CH-arom.; 8.14, s, 1H, CH═N; 8.30, b, 2H, NH; 9.83, d, J=8 Hz, 1H,NH.

8: 1.20, t, J=7.1 Hz, 3H, CH₃; 3.5, b, 4H, N—CH₂; 3.55 and 4.51,AB-quartet, J=18.2 Hz, 2H, S—CH₂; 3.6, b, 4H, N—CH₂; 4.07, q, J=7.1 Hz,2H, O—CH₂; 5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.88, dd, J=5.0 Hz andJ=7.9 Hz, 1H, b-lactam-H; 6.84, s, 1H, CH thiazol; 8.4, b, 2H, NH; 8.66,s, 1H, CH═N; 9.72, d, J=7.9 Hz, 1H, NH; 12.3, b, 1H, OH; 12.4, b, 1H,OH.

9: 3.4-3.8, m,b, 8H, N—CH₂; 3.56 and 4.53, AB-quartet, J=18 Hz, 2H,S—CH₂; 3.8-4.0, m, 2H, N—CH₂; 5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.88,dd, J=5.0 Hz and J=7.9 Hz, 1H, β-lactam-H; 6.84, s, 1H, CH thiazol;8.2-8.5, b, 4H, NH; 8.69, s, 1H, CH═N; 9.72, d, J=7.9 Hz, 1H, NH;10.1-10.3, b, 1H, NH; 12.4, b, 2H, OH.

10: 3.56 and 4.52, AB-quartet, J=18.0 Hz, 2H, S—CH₂; 3.7, b, 8H, N—CH₂;5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.89, dd, J=5.0 Hz and J=7.8 Hz, 1H,β-lactam-H; 6.85, s, 1H, CH thiazol; 7.4-7.5, m, 5H, CH arom.; 8.4, b,2H, NH; 8.67, s, 1H, CH═N; 9.74, d, J=7.8 Hz, 1H, NH; 12.3, b, 1H, OH;12.4, b, 1H, OH.

11: 2.04, s, 3H, CH₃; 3.55 and 4.53, AB-quartet, J=18.0 Hz, 2H, S—CH₂;3.6, b, 8H, N—CH₂; 5.31, d, J=5.0 Hz, 1H, β-lactam-H; 5.90, dd, J=5.0 Hzand J=7.9 Hz, 1H, β-lactam-H; 6.84, s, 1H, CH thiazol; 8.3, b, 2H, NH;8.62, s, 1H, CH═N; 9.79, d, J=7.9 Hz, 1H, NH, 12.1, b, 1H, OH; 12.4, b,1H, OH.

12: 3.55 and 4.53, AB-quartet, J=18.0 Hz, 2H, S—CH₂; 3.6, b, 8H, N—CH₂;3.77, s, 2H, C—CH₂; 5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.89, dd, J=5.0Hz and J=7.9 Hz, 1H, β-lactam-H; 6.84, s, 1H, CH thiazol; 7.2-7.4, m,5H, CH arom.; 8.3, b, 2H, NH; 8.64, s, 1H, CH═N; 9.78, d, J=7.9 Hz, 1H,NH; 12.2, b, 1H, OH; 12.5, b, 1H, OH.

13: 3.3-3.5, m, 2H, N—CH₂; 3.56 and 4.50, AB-quartet, J=18.0 Hz, 2H,S—CH₂; 3.6-3.8, m,b, 6H, N—CH₂; 5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.89,dd, J=5.0 Hz and J=7.9 Hz, 1H, β-lactam-H; 6.84, s, 1H, CH thiazol;6.97, s, 1H, CH thiazol; 8.4, b, 2H, NH; 8.64, s, 1H, CH═N; 9.71, d,J=7.9 Hz, 1H, NH; 12.2, b, 2H, OH; 12.3, b, 1H, OH.

14: 2.77, s, 6H, N—CH₃; 3.1-3.3, m, 4H, N—CH₂; 3.56 and 4.51,AB-quartet, J=18.0 Hz, 2H, S——CH₂; 3.5-3.7, m, 4H, N—CH₂; 5.30, d, J=5.0Hz, 1H, β-lactam-H; 5.89, dd, J=5.0 Hz and J=7.8 Hz, 1H, β-lactam-H;6.85, s, 1H, CH thiazol; 8.3, b, 2H, NH; 8.65, s, 1H, CH═N; 9.74, d,J=7.8 Hz, 1H, NH; 12.2, b, 1H, OH; 12.4, b, 1H, OH.

15: 3.5-3.8, m,b, 8H, N—CH₂; 3.56 and 4.52, AB-quartet, J=18 Hz, 2H,S—CH₂; 4.87, s, 2H, O—CH₂; 5.31, d, J=4.9 Hz, 1H, β-lactam-H; 5.89, dd,J=5.0 Hz and J=7.8 Hz, 1H, β-lactam-H; 6.83, s, 1H, CH thiazol; 6.9-7.0,m, 3H, CH arom.; 7.2-7.4, m, 2H, CH arom.; 8.3, b, 2H, NH; 8.65, s, 1H,CH═N; 9.70, d, J=7.8 Hz, 1H, NH; 12.2, b, 1H, OH; 12.3, b, 1H, OH.

16: 1.7-2.0, m, 3H, C—CH₂; 2.3-2.5, m, 1H, C—CH₂; 3.1-3.3, m, 2H, N—CH₂;3.3-3.9, m,b, 8H, N—CH₂; 3.56 and 4.50, AB-quartet, J=18.1 Hz, 2H,S—CH₂; 4.64.8, m, 1H, N—CH; 5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.90, dd,J=5.0 Hz and J=7.9 Hz, 1H, β-lactam-H; 6.79, s, 1H, CH thiazol; 8.3, b,2H, NH; 8.5, b, 2H, NH; 8.63, s, 1H, CH═N; 9.63, d J=7.9 Hz, 1H, NH;10.1-10.3, b, 1H, NH; 12.0, b, 1H, OH; 12.2, b, 1H, OH.

17: 2.25, s, 3H, CH₃; 3.3, b, 2H, N—CH₂; 3.56 and 4.52, AB-quartet, J=18Hz, 2H, S—CH₂; 3.6, b, 2H, N—CH₂; 3.7, b, 4H, N—CH₂; 5.30, d, J=5.0 Hz,1H, β-lactam-H; 5.89, dd, J=5.0 Hz and J=7.8 Hz, 1H, β-lactam-H; 6.85,s, 1H, CH thiazol; 7.2-7.4, m, 4H, CH arom.; 8.4, b, 2H, NH; 8.66, s,1H, CH═N; 9.74, d, J=7.9 Hz, 1H, NH; 12.3, b, 1H, OH; 12.4, b, 1H, OH.

18: 3.2, b, 2H, N—CH₂; 3.53 and 4.58, AB-quartet, J=18.2 Hz, 2H, S—CH₂;3.5, b, 4H, N—CH₂; 3.8, b, 2H, N—CH₂; 5.29, d, J=5.0 Hz, 1H, β-lactam-H;5.7, m,b, 1H, N—CH; 5.88, dd, J=5.0 Hz and J=8.0 Hz, 1H, β-lactam-H;6.81, s, 1H, CH thiazol; 7.4-7.6, m, 5H, CH arom.; 8.3, b, 2H, NH; 8.62,s, 1H, CH═N; 8.8, b, NH; 9.67, d, J=8.0 Hz, 1H, NH; 12.2, b, 2H, OH.

19: 3.0-3.3, m,b, 2H, N—CH₂; 3.5-3.8, m,b, 6H, N—CH₂; 3.53 and 4.47,AB-quartet, J=18.3 Hz, 2H, S—CH₂; 5.29, d, J=5.1 Hz, 1H, β-lactam-H;5.5, m, 1H, N—CH; 5.88, dd, J=5.0 Hz and J=7.9 Hz, 1H, β-lactam-H; 6.81,s, 1H, CH thiazol; 6.8-6.9, m, 2H, CH arom.; 7.2-7.4, m, 2H, CH arom.;8.3, b, 2H, NH; 8.5, b, 3H, NH; 8.60, s, 1H, CH═N; 9.67, d, J=7.9 Hz,1H, NH; 12.2, b, 2H, OH.

20: 1.5-1.9, m, 4H, C—CH₂; 3.1-3.3, m,b, 2H, N—CH₂; 3.5-3.9, m,b, 8H,N—CH₂; 3.56 and 4.51, AB-quartet, J=18.1 Hz, 2H, S—CH₂; 4.48, 1H, N—CH;5.30, d, J=5.1 Hz, 1H, β-lactam-H; 5.89, dd, J=5.0 Hz and J=7.9 Hz, 1H,β-lactam-H; 6.82, s, 1H, CH thiazol; 8.1, b, 2H, NH; 8.4, b, NH; 8.65,s, 1H, CH═N; 9.69, d, J=7.9 Hz, 1H, NH; 12.2, b, 2H, OH.

21: 3.4-3.7, m,b, 9H, N—CH₂/S—CH₂; 4.13, s, 2H, O—CH₂; 4.50, J=18.1 Hz,1H, S—CH₂; 5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.89, dd, J=5.0 Hz andJ=7.9 Hz, 1H, β-lactam-H; 6.81, s, 1H, CH thiazol; 8.3, b, 2H, NH; 8.62,s, 1H, CH═N; 9.67, d, J=7.9 Hz, 1H, NH; 12.1, b, 2H, OH.

22: 1.4-1.9, m, 4H, C—CH₂; 3.1-3.3, m,b, 2H, N—CH₂; 3.5-4.0, m,b, 8H,N—CH₂; 3.56 and 4.52, AB-quartet, J=18.0 Hz, 2H, S—CH₂; 4.49, b, 1H,N—CH; 5.30, d, J=5.1 Hz, 1H, β-lactam-H; 5.89, dd, J=5.1 Hz and J=7.9Hz, 1H, β-lactam-H; 6.81, s, 1H, CH thiazol; 8.11, m, 1H, NH; 8.4, b,NH; 8.67, s, 1H, CH═N; 9.68, d, J=7.8 Hz, 1H, NH; 12.2, b, 1H, OH; 12.3,b, 1H, OH.

23: 1.8-2.1, m,b, 2H, C—CH₂; 2.3-2.6, m,b, 2H, C—CH₂; 3.4-3.9, m,b, 8H,N—CH₂; 3.55 and 4.52, AB-quartet, J=18 Hz, 2H, S—CH₂; 4.4, m,b, 1H,N—CH; 5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.88, dd, J=5.0 Hz and J=7.9Hz, 1H, β-lactam-H; 6.81, s, 1H, CH thiazol;

8.4, b, NH; 8.67, s, 1H, CH═N; 9.69, d, J=8.0 Hz, 1H, NH; 12.2, b, 1H,OH; 12.3, H, OH.

24: 0.87, t, J=7.3 Hz, 3H, CH₃; 0.94, d, J=6.7 Hz, 3H, CH₃; 1.0-1.3, m,1H, C—CH₂, C—CH; 1.4-1.6, m, 1H, C—CH₂, C—CH; 1.7-1.9, m, 1H, C—CH₂,C—CH; 3.44.0, m,b, 8H, N—CH₂; 3.55 and 4.51, AB-quartet, J=18.0 Hz, 2H,S—CH₂; 4.31, m, 1H, N—CH; 5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.89, dd,J=5.0 Hz and J=7.9 Hz, 1H, β-lactam-H; 6.81, s, 1H, CH thiazol; 8.3, b,NH; 8.67, s, 1H, CH═N; 9.68, d, J=7.9 Hz, 1H, NH; 12.2, b, 1H, OH; 12.4,b, 1H, OH.

25: 0.85, b, 3H, CH₃; 1.2, b, 6H, C—CH₂; 1.5, b, 2H, C—CH₂; 2.33, t,b, 7Hz, 2H, C—CH₂; 3.3-3.8, m,b, 9H, N—CH₂, S—CH₂; 4.54, J=18.1 Hz, 1H,S—CH₂; 5.30, d, J=4.9 Hz, 1H, β-lactam-H; 5.89, dd, J=5 Hz and J=8 Hz,1H, β-lactam-H; 6.85, s, 1H, CH thiazol; 8.4, b, NH; 8.66, s, 1H, CH═N;9.79, d, J=7.8 Hz, 1H, NH; 12.3, b,1H,OH; 12.5, b,1H, OH.

26: 0.84, t,b, J=6.5 Hz, 3H, CH₃; 1.2, b, 28H, C—CH₂; 1.47, m,b, 2H,C—CH₂; 2.33, t, J=7 Hz, 2H, C—CH₂; 3.4-3.8, m,b, 9H, N—CH₂, S—CH₂; 4.53,J=18.0 Hz, 1H, S—CH₂; 5.31, d, J=4.9 Hz, 1H, β-lactam-H; 5.90, dd, J=5Hz and J=8 Hz, 1H, β-lactam-H; 6.85, s, 1H, CH thiazol; 8.4, b, 2H, NH;8.65, s, 1H, CH═N; 9.78, d, J=7.9 Hz, 1H, NH; 12.2, b, 1H, OH; 12.4, b,1H, OH.

27: 0.85, t, J=6 Hz, 3H, CH₃; 1.24, 24H, C—CH₂; 1.5, m,b, 2H, C—CH₂;2.33, t, J=7 Hz, 2H, C—CH₂; 3.4-3.7, m,b, 9H, N—CH₂, S—CH₂; 4.52, J=18.0Hz, 1H, S—CH₂; 5.31, J=5.0 Hz, 1H, β-lactam-H; 5.90, dd, J=5 Hz and J=8Hz, 1H, β-lactam-H; 6.83, s, 1H, CH thiazol; 8.3, b, 2H, NH; 8.61, s,1H, CH═N; 9.74, d, J=7.9 Hz, 1H, NH; 12.1, b, 1H, OH; 12.3, b, 1H, OH.

28: 0.86, t, J=6.5 Hz, 3H, CH₃; 1.26, 8H, C—CH₂; 1.49, m,b, 2H, C—CH₂;2.33, t, J=7 Hz, 2H, C—CH₂; 3.4-3.8, m,b, 9H, N—CH₂, S—CH₂; 4.52,J=18.1Hz, 1H, S—CH₂; 5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.89, dd, J=5.0 Hz andJ=7.8 Hz, 1H, β-lactam-H; 6.79, s, 1H, CH thiazol; 8.3, b, 2H, NH; 8.62,s, 1H,CH═N; 9.69,d, J=7.8 Hz, 1H, NH; 12.1, b, 2H, OH.

29: 3.3-3.9, m,b, 11H, N—CH₂, S—CH₂, O—CH₂; 4.37, t, J=5.5 Hz, 1H, O—CH;4.50, J=18.9 Hz, 1H, S—CH₂; 5.30, d, J=5.0 Hz, 1H, β-lactam-H; 5.90, dd,J=5.0 Hz and J=7.9 Hz, 1H, β-lactam-H; 6.83, s, 1H, CH thiazol; 8.3, b,2H, NH; 8.62, s, 1H, CH—N; 9.70, d, J=7.9 Hz, 1H, NH; 12.1, b, 1H, OH;12.3, b, 1H, OH.

30: 3.5-3.8, m,b, 8H, N—CH₂; 3.51 and 4.54, AB-quartet, J=18.1 Hz, 2H,S—CH₂; 4.87, s, 2H, O—CH₂; 5.29, d, J=5.1 Hz, 1H, β-lactam-H; 5.79, d,J=55.6 Hz, 2H, F—CH₂; 5.92, dd, J=5.0 Hz and J=8.1 Hz, 1H, β-lactam-H;6.9-7.0, m, 3H, CH arom.; 7.2-7.4, m, 2H, CH arom.; 8.3, b, NH; 8.64, s,1H, CH═N; 9.81, d, J=8.2 Hz, 1H, NH; 12.2, b, 1H, OH.

31: 2.25, s, 3H, CH₃; 3.2-3.9, m,b, 8H, N—CH₂; 3.51 and 4.52,AB-quartet, J=18.2 Hz, 2H, S—CH₂; 5.29, d, J=5.0 Hz, 1H, β-lactam-H;5.79, d, J=55.0 Hz, 2H, F—CH₂; 5.92, dd, J=5 Hz and J=8 Hz, 1H,β-lactam-H; 7.2-7.6, m, 4H, CH arom.; 8.1-8.5, b, 4H, NH; 8.61, s, 1H,CH═N; 9.80, d, J=8.3 Hz, 1H, NH; 12.2, b, 1H, OH.

32: 2.04,s,3H, CH₃; 3.3-3.8,m,b, 9H, N—CH₂,S—CH₂; 4.55, J=1 8.2 Hz, 1H,S—CH₂5.29, d, J=5.0 Hz,1H,β-lactam-H; 5.79,d, J=56.0 Hz,2H,F—CH₂;5.93,dd, J=5 Hz and J=8 Hz,1H, β-lactam-H; 8.3,b, NH; 8.62, s, 1H, CH═N;9.84, d, J=8.2 Hz, 1H, NH; 12.2, b,1H, OH.

33: 1.7-2.0, m, 3H, C—CH₂; 2.2-2.5, m, 1H, C—CH₂; 3.1-3.4, m, 2H, N—CH₂;3.3-3.9, m,b, 8H, N—CH₂; 3.50 and 4.54, AB-quartet, J=18.2 Hz, 2H,S—CH₂; 4.64.8, m, 1H, N—CH; 5.28, d, J=5.0 Hz, 1H, β-lactam-H; 5.78, d,J=57.8 Hz, 2H, F—CH₂; 5.90, dd, J=5.0 Hz and J=8.2 Hz, 1H, β-lactam-H;8.5, b, NH; 8.68, s, 1H, CH═N; 9.81, d, J=7.9 Hz, 1H, NH; 10.4, b, 1H,NH; 12.5, b, 1H, OH.

34: 3.4-3.8, m,b, 8H, N—CH₂; 3.50 and 4.55, AB-quartet, J=18.2 Hz, 2H,S—CH₂; 3.9, m, 2H, N—CH₂; 5.28, d, J=5.0 Hz, 1H, β-lactam-H; 5.78, d,J=56.7 Hz, 2H, F—CH₂; 5.91, dd, J=5.0 Hz and J=8.3 Hz, 1H, β-lactam-H;8.3, b, NH; 8.68, s, 1H, CH═N; 9.81, d, J=8.3 Hz, 1H, NH; 12.4, b, 1H,OH.

35: 0.85,t, J=7.2 Hz, 3H,CH₃; 0.92,d, J=6.8 Hz, 3H,CH₃; 1.0-1.3,m,1H,C—CH₂, C—CH; 1.4-1.6,m,1H, C—CH₂, C—CH; 1.7-1.9, m,1H,C—CH₂,C—CH;3.3-4.0,m,b,8H, N—CH₂; 3.50 and 4.54, AB-quartet, J=8.2 Hz, 2H, S—CH₂;4.30, m,b, 1H, N—CH; 5.28, d, J=5.0 Hz, 1H, β-lactam-H; 5.78, d, J=58.1Hz, 2H, F—CH₂; 5.90, dd, J=5.0 Hz and J=8.2 Hz, 1H, β-lactam-H; 8.4, b,NH; 8.68, s, 1H, CH═N; 9.81, d, J=7.9 Hz, 1H, NH; 12.4, b, 1H, OH.

36: 3.1-3.3, m,b, 2H, N—CH₂; 3.5-3.8, m,b, 6H, N—CH₂; 3.48 and 4.51,AB-quartet, J=18.3 Hz, 2H, S—CH₂; 5.27, d, J=5.1 Hz, 1H, β-lactam-H;5.5, m,b, 1H, N—CH; 5.78, d, J=58.3 Hz, 2H, F—CH₂; 5.90, dd, J=5.0 Hzand J=8.3 Hz, 1H, β-lactam-H; 6.8-7.0, m, 2H, CH arom.; 7.2-7.4, m, 2H,CH arom.; 8.3, b, NH; 8.62, s, 1H, CH═N; 9.80, d,J=8.3 Hz, 1H, NH; 12.3,b, 1H, OH.

37: 3.48 and 4.55, AB-quartet, J=18.1 Hz, 2H, S—CH₂; 3.6, b, 4H, N—CH₂;3.7, b, 4H, N—CH₂; 5.28, d, J=4.9 Hz, 1H, β-lactam-H; 5.6, b, 1H, CH₂F;5.8-6.0, m, 2H, CH₂F and β-lactam-H; 7.9, b, NH; 8.3, b, NH; 8.64, s,1H, CH═N; 9.5, b, NH; 9.83, d, J=8,3 Hz, 1H, NH.

38: 1.21, t, 3H, J=7 Hz, CH₃; 2.0-2.2, m, 2H, NCH₂—CH₂—CH₂N; 2.73, s,3H, N—CH₃; 2.76, s, 3H, N—CH₃; 3.0-3.4, m, 6H, N—CH₂; 3.4-3.7, m, 5H, 4N—CH₂ and 1 S—CH₂, as part of AB-quartet; 3.57-4.0,m,4H,N—CH₂; 4.59, 1Has part of AB-quartet of S—CH₂, J=18.2 Hz; 5.31, d, J=5.0 Hz, 1H,β-lactam-H; 5.81, d, J=55 Hz, 2H, CH₂F; 5.95, dd, J=5 Hz and 8.2 Hz,β-lactam-H; 8.7, s, 1H, CH═N; 9.86, d, J=8,2 Hz, 1H, NH.

39: 3.55 and 4.53, AB-quartet, J=18.1 Hz, 2H, S—CH₂; 3.6, b, 4H, N—CH₂;3.7, b, 4H, N—CH₂; 5.30, d, J=5.1 Hz, 1H, β-lactam-H; 5.88, dd, J=5.1 Hzand J=7.8 Hz, 1H, β-lactam-H; 6.84, s, 1H, CH thiazol; 7.9, b, NH; 8.4,b, NH; 8.70, s, 1H, CH═N; 9.74, d, J=8.0 Hz, 1H, NH; 12.4, b, 2H, OH.

40: 2.3-2.7, m, 4H, C—CH₂; 3.3-3.8, m, 9H, N—CH₂ and S—CH₂, 4.52, partof AB-quartet, J=18.1 Hz, 1H, S—CH₂; 5.31, d, J=5.0 Hz, 1H, β-lactam-H;5.90, dd, J=5.0 Hz and J=7.8 Hz, 1H, β-lactam-H; 6.83, s, 1H, CHthiazol; 8.3, b, NH; 8.61, s, 1H, CH═N; 9.75, d, J=7.9 Hz, 1H, NH; 12.1,b, 1H, OH; 12.3, b, 1H, OH.

41: 0.6-0.9, m, 4H, CH₂cycl.; 1.8-2.1, m, 1H, CH cycl.; 3.3-3.9, mb, 9H,N—CH₂ and S—CH₂, 4.52, part of AB-quartet, J=18.0 Hz, 1H, S—CH₂; 5.31,d, J=5.0 Hz, 1H, β-lactam-H; 5.90, dd, J=5.0 Hz and J=7.8 Hz, 1H,β-lactam-H; 6.84, s, 1H, CH thiazol; 8.3, b, NH; 8.63, s, 1H, CH═N;9.71, d, J=7.9 Hz, 1H, NH; 12.1, b, 1H, OH; 12.3, b, 1H, OH.

42: 3.56 and 4.53, AB-quartet, J=18.2 Hz, 2H, S—CH₂; 3.7, b, 11H, N—CH₂and O—CH₃; 3.80, s, 6H, O—CH₃; 5.31, d, J=5.0 Hz, 1H, β-lactam-H; 5.90,dd, J=5 Hz and J=7.7 Hz, 1H, β-lactam-H; 6.75, s, 2H, CH arom.; 6.83, s,1H, CH thiazol; 8.4, b, NH; 8.65, s, 1H, CH═N; 9.76, d, J=7.8 Hz, 1H,NH; 12.3, b, 1H, OH; 12.4, b, 1H, OH.

43: 3.51 and 4.54, AB-quartet, J=18.2 Hz, 2H, S—CH₂; 3.5-3.8, b, 11H,N—CH₂and O—CH₃; 3.80, s, 6H, O—CH₃; 5.29, d, J=5.0 Hz, 1H, β-lactam-H;5.65, b, 1H, CH₂F; 5.8-6.0, m, 2H, CH₂F and β-lactam-H; 6.74, s, 2H, CHarom.; 8.3, b, NH; 8.63, s, 1H, CH═N; 9.84, d, J=8.2 Hz, 1H, NH; 12.2,b, 1H, OH/NH.

44: 1.26, d, J=7.2 Hz, 3H, C—CH₃; 3.2-3.7, m b, 9H, N—CH₂ and S—CH₂;3.9-4.1, m, 1H, N—CH; and 4.27, part of AB-quartet, J=17.5 Hz, 1H,S—CH₂; 5.15, d, J=4.9 Hz, 1H, β-lactam-H; 5.71, dd, J=4.9 Hz and J=7.9Hz, 1H, β-lactam-H; 6.6, s, 1H, CH thiazol; 7.1, b, NH; 8.59, s, 1H,CH═N; 9.48, d, J=7.9 Hz, 1H, NH; 11.3, b, 1H, OH.

45: 1.23, d, J=7.2 Hz, 3H, C—CH₃; 3.2-3.7, m b, 9H, N—CH₂ and S—CH₂;3.9-4.1, m, 1H, N—CH; and 4.28, part of AB-quartet, J=17.5 Hz,1H, S—CH₂;5.16, d, J=5 Hz, 1H, β-lactam-H; 5.70, dd, J=5 Hz and J=7.9 Hz, 1H,β-lactam-H; 6.7, s, 1H, CH thiazol; 7.1, b, NH; 8.58, s, 1H, CH═N; 9.43,d, J=7.9 Hz, 1H, NH; 11.3, b, 1H, OH.

46: Diastereomer A: 1.26 (d, J=6 Hz, 6H); 1.58 (d, J=5.3 Hz, 3H,—O(CH₃)CH—O—); 2.06 (s, 3H, CH₃CO); 3,5 -3,7 (m, 9 H, 8 N—CH₂ and 1S—CH₂ as part of AB-quartet); 4.4-4.9 (m, 2 H, —O—CH(CH₃)₂ and 1 S—CH₂as part of AB-quartet); 5,35 (d, J=5,7 Hz, 1H, β-lactam-H); 5,81 (d,J=56 Hz, 2H, CH₂F); 6,0 (dd, J=5 and 8,2 Hz, 1H, β-lactam-H); 6,95 (q,1H, O(CH₃)CH—O—); 8,7 (s, 1H, CH═N), (broad singulet, 2H, NH₂); 9,86 (d,J=8,2 Hz, 1H, NH).

Diastereomer B: 1.26 (d, J=6 Hz, 6H); 1.55 (d, J=5.3 Hz, 3H,—O(CH₃)CH—O—); 2.06 (s, 3H, CH₃CO); 3,5 -3,7 (m, 9 H, 8 N—CH₂ and 1S—CH₂ as part of AB-quartet); 4.4-4.9 (m, 2 H, —O—CH(CH₃)₂ and 1 S—CH₂as part of AB-quartet); 5,32 (d, J=5,7 Hz, 1H, β-lactam-H); 5,81 (d,J=56 Hz, 2H, CH₂F); 6,0 (dd, J=5 and 8,2 Hz, 1H, β-lactam-H); 6,85(q,1H,O(CH₃)CH—O—);8,6 (s,1H,CH═N); 0,85 (d, J=8,2 Hz,1H, NH).

47: Diastereomer A: 1.24 (d, J=6 Hz, 6H); 1.53 (d, J=5.4 Hz, 3H,—O(CH₃)CH—O—); 3.88 (broad singulet, 4H); 4.0 (broad singulet, 4H); 4.10(AB-quartet, J=18.4 Hz, S—CH₂); 4.78 (q, 1H, —O—CH(CH₃)₂); 5.3 (d, J=5.1Hz, 1H, β-lactam-H); 5.78 (d, J=55 Hz, 2H, CH₂F); 5.96 (dd, J=5.1 and8.4 Hz, 1H, β-lactam-H); 6.81 (q, 1H, O(CH₃)CH—O—); 8.6 (s, 1H, CH═N);(broad singulet, 2H, NH₂); 9.79 (d, J=8,4 Hz, 1H, NH).

Diastereomer B: 1.25 (d, J=6 Hz, 6H); 1.56 (d, J=5.4 Hz, 3H,—O(CH₃)CH—O—); 3.88 (broad singulet, 4H); 4.0 (broad singulet, 4H); 4.11(AB-quartet, J=18.4 Hz, S—CH₂); 4.80 (q, 1H, —O—CH(CH₃)₂); 5.33 (d,J=5.1 Hz, 1H, β-lactam-H); 5.78 (d, J=55 Hz, 2H, CH₂F); 5.99 (dd, J=5.1and 8.4 Hz, 1H, β-lactam-H); 6.92 (q, 1H, O(CH₃)CH—O—); 8.7 (s, 1H,CH═N): 9.81 (d,J=8.4 Hz, 1H, NH).

48: Diasteromer A: 1.25, d,J=6.2 Hz, 6H; 1.53, d, J=5.3 Hz, 3H,—O(CH₃)CH—O—; 2.08, s, 3H, CH₃CO; 3.1-3.3, m, 2H, N—CH₂; 3,5-3,7, m, 9H, 8 N—CH₂ and 1 S—CH₂ as part of AB-quartet; 4.5-4.9, m, 2 H,—O—CH(CH₃)₂ and 1 S—CH₂ as part of AB-quartet; 5,31, d, J=5,5 Hz, 1H,β-lactam-H; 5,80, d, J=55 Hz, 2H, CH₂F; 5.98, dd, J=5 and 8,2 Hz, 1H,β-lactam-H; 6,7-7,0, m, 3H, O(CH₃)CH—O— and 2 CH aromat.; 7,32, d,J=8.5, 2H, CH arom.; 8.59, s, 1H, CH═N; 9,84, d, J=8,3 Hz, 1H, NH.

Diastereomer B: 1.25, d, J=6 Hz, 6H; 1.57, d,J=5.3 Hz, 3H, —O(CH₃)CH—O—;2.09, s, 3H, CH₃CO; 3.1-3.3, m, 2H, N—CH₂; 3,5-3,7, m, 9 H, 8 N—CH₂ and1 S—CH₂ as part of AB-quartet; 4.5-4.9, m, 2 H, —O—CH(CH₃)₂ and 1 S—CH₂as part of AB-quartet; 5,34, d, J=5,8 Hz, 1H, β-lactam-H; 5,80, d, J=55Hz, 2H, CH₂F; 5,98, dd, J=5 and 8,2 Hz, 1H, β-lactam-H; 6,7-7,0, m, 3H,O(CH₃)CH—O— and 2 CH aromat.; 7,32, d, J 8.5, 2H, CH arom.; 8,69, s, 1H,CH═N; 9.85, d, J=8,2 Hz, 1H, NH.

49: Diastereomer A: 1.16, s, 9H, C—CH₃; 3.46 and 3.92, AB-quartet,J=18.0 Hz, S—CH₂; 5.33, d, J=5.3 Hz, 1H, β-actam-H; 5.78, d, J=55 Hz,2H, CH₂F; 5.90 and 5.98, AB-quartet, J=6.04 Hz, OCH₂O—; 6.06, dd, J=5.3and 8.3 Hz, 1H, β-lactam-H; 8.2, broad singulet, 2H, NH₂; 9.65, s, 1H,CH═O; 9.88, d, J=8,3 Hz, 1H, NH.

Diastereomer B: 1.18, s, 9H, C—CH₃; 3.1-3.3, m, 2H, N—CH₂; 3.4-3.8, m,6H, N—CH₂; 3.5 and 4.65, AB-quartet, J=18.5 Hz, S—CH₂; 5.34, d, J=5.0Hz, 1H, β-actam-H; 5.66, m, 1H, N—CH; 5.79, d, J=55 Hz, 2H, CH₂F;5.7-6.0, m, 3H, OCH₂O— and β-lactam-H; 6.88 and 7.32, d and d, J=8.4 andJ=8.5, 4H, CH arom.; 8.75, s, 1H, CH═N; 9.87, d, J=8,2 Hz, 1H, NH.

Aa: 2,55 (s, 3H, S—CH₃); 3,45 (s, 3H, N—CH₃).

Ab: 3,4 (s, 3H, N—CH₃); 3,51 (m, 2H) and 3,58 (m, 6H, —CH₂—N—CH₂—);7,45-7,48 (m, 3H, CH arom.); 7,81-7,85 (m, 2H, CH arom.); 8,10 (s, 1H,N—CH═O); 8,14 (s, 1H, CH═N); 9,0 (broad singulet, 2H, N⁺H₂).

Ac: 3,16 (m, 7H, N—CH₃ and —CH₂—N—CH₂—); 3,61 (m, 4H, —CH₂—N⁺—CH₂—); 6.0(broad singulet, 3H, N⁺H₃); 8,3 (broad singulet, 1H, NH); 10.0 (broadsingulet, 2H, N⁺H₂).

B: 1.22, t, J=5 Hz, 3H, CH₃; 3.16, b, 4H, N—CH₂; 3.45, q, J=5 Hz, 2H,CH₂; 3.65, b, 4H, N—CH₂; 10.14, b, 2H, NH.

C: 3.14, b, 4H, N—CH₂; 3.68, b, 4H, N—CH₂; 3.98-4.18, m, 2H, CH₂—C;5.16-5.48, m, 2H, CH₂═C; 5.80-6.10, m, 1H, CH═C; 10.30, b, 2H, NH.

D: 3.19, b, 4H, N—CH₂; 3.67, b, 4H, N—CH₂; 3.77, s, 3H, O—CH₃; 4.59, s,2H, N—CH₂; 6.90-7.02 and 7.25-7.38, m, each 2H, CH-arom.; 10.02, b, 2H,NH.

E: 3.20, b, 4H, N—CH₂; 3.67, b, 7H, 4H of N—CH₂ and 3H of O—CH₃; 3.81,s, 6H, O—CH₃; 4.59, s, 2H, N—CH₂; 6.69, s, 2H, CH-arom.; 9.96, b, 2H,NH.

F: 2.84, s, 3H, CH₃; 3.18, b, 7H, 4H of N-CH₂ and 3H of CH₃; 3.63, b,4H, N—CH₂; 10.13 b, 2H, NH.

G: 1.20, t, J=5 Hz, 3H, CH₃; 3.19, b, 9H, 4H of N—CH₂ and 3H of CH₃ and2H of CH₂; 3.64, b, 4H, N—CH₂; 10.12, b, 2H, NH.

La: 3.32 and 3.70 (AB Quartet, J=17 Hz, 2H, SCH₂); 5.22 (d, J=5 Hz, 1H,β-lactam-H); 5.82 (d, J=55 Hz, 2H, CH₂F); 5.86 (dd, J=5 and 8,4 Hz, 1H,β-lactam-H); 8.35 (broad singulet, 2H, NH₂); 9.5 (s, 1H, CH═O); 9.88 (d,J=8,4 Hz, 1H, NH).

Lb: Diastereomer A: 1.21 (d, J=6 Hz, 6H); 1.53 (d,J=5.4 Hz, 3H,—O(CH₃)CH—O—); 3.67 (AB-quartet, J=18.2 Hz, S—CH₂); 4.64.9 (m, 2H,—O—CH(CH₃)₂; 5.32 (d, J=5.3 Hz, 1H, β-lactam-H); 5.8 (d, J=55 Hz, 2H,CH₂F); 6.04 (dd, J=5.3 and 8.4 Hz, 1H, β-lactam-H); 6.84 (q, 1H,O(CH₃)CH—O—); 8.2 (broad singulet, 2H, NH₂); 9.6 (s, 1H, CH═O); (broadsingulet, 2H, NH₂); 9.88 (d, J=8,4 Hz, 1H, NH).

Diastereomer B: 1.23 (d, J=6 Hz, 6H); 1.53 (d, J=5.4 Hz, 3H,—O(CH₃)CH—O—); 3.68 (AB-quartet, J=18.2 Hz, S—CH₂); 4.6-4.9 (m, 1H,—O—CH(CH3)₂; 5.33 (d, J=5.3 Hz, 1H, β-lactam-H); 5.8 (d, J=55 Hz, 2H,CH₂F); 6.08 (dd, J=5.3 and 8.4 Hz, 1H, β-lactam-H); 6.93 (q, 1H,O(CH₃)CH—O—); 9.6 (s, 1H, CH═O): 9.88 (d, J=8.4 Hz, 1H, NH).

1-15. (canceled)
 16. A compound of the formula

wherein R₁ is hydrogen, acyl, carboxyl, or alkyl; R₂ and R₃ are the sameor different and independently of each other are hydrogen, cycloalkyl,alkyl, alkenyl, or alkinyl; R₄ is hydrogen or a group of the formula

wherein R₆ is amino, hydrazino, aminoalkylamino, alkoxy, aryl,cycloalkyl, aryloxy, heterocyclyl, allyl, alkenyl, or alkinyl; and Z isO, S, or NR₇, wherein R₇ is as defined as R₂; R₅ is hydrogen or an eatermoiety; W is CH or N; and V is CH or N—O; with the proviso that not allof R₂, R₃, and R₄ denote hydrogen and that if R₄ denotes hydrogen, thenR₁ other than hydrogen or CH₃; and with the further proviso thatcompounds of formula I wherein a) V is N—O, W is CH, R₁ is CH₃, R₂ is H,R₃ is CH₃, and R₄ is H; b) V is N—O, W is CH, R₁ is CH₃, R₂ is H, R₃ isH, and R₄ is H; c) V is N—O, W is CH, R₁ is CH₃, R₂ is CH₃, R₃ is H, andR₄ is H; d) V is N—O, W is CH, R₁ is H, R₂ is H, R₃ is H, and R₄ is H;e) V is N—O, W is CH, R₁ is H, R₂ is CH₃, R₃ is H, and R₄ is H; and f) Vis N—O, W is N, R₁ is CH₂F, R₂ is H, R₃ is H, and R₄ is H; are excluded.17. A compound of claim 16 of the formula

wherein R′₁ is hydrogen or alkyl; R′₂ and R′₃ are the same or differentand independently of each other are hydrogen, alkenyl, or alkyl; and R′₄is hydrogen or a group of the formula

wherein Z′ is O or NR′₇, wherein R′₇ is hydrogen or alkyl; and R′₆ isamino; aminoalkylamino; hydrazino; alkoxy; unsubstituted aryl orsubstituted aryl; cycloalkyl; a 5 to 6 membered heterocycle containing 1to 3 nitrogen and/or sulphur- and/or oxygen atoms; unsubstituted alkyl;alkyl, one or several-fold substituted by unsubstituted aryl, or by arylwhich is in turn substituted by hydroxy, alkoxy, phenoxy, aryloxy,amino, hydroxyl, carboxy, guanidino or nitroguanidino; or aheterocyclyl-carboximino group; with the proviso that not all of R′₂,R′₃, and R′₄ denote hydrogen and that if R′₄ denotes hydrogen, then R′₁is other than hydrogen or CH₃; and with the further proviso thatcompounds of formula Ia wherein a) W is CH, R′₁ is CH₃, R′₂ is H, R′₃ isCH₃, and R′₄ is H; b) W is CH, R′₁ is CH₃, R′₂ is H, R′₃ is H, and R′₄is H; c) W is CH, R′₁ is CH₃, R′₂ is CH₃, R′₃ is H, and R′₄ is H; d) Wis CH, R′₁ is H, R′₂ is H, R′₃ is H, and R′₄ is H; e) W is CH, R′₁ is H,R′₂ is CH₃, R′₃ is H, and R′₄ is H; and f) W is N, R′₁ is CH₂F, R′₂ isH, R′₃ is H, and R′₄ is H; are excluded.
 18. A compound of claim 16 ofthe formula


19. A compound of claim 16 of the formula

wherein R_(2p) and R_(3p) are the same or different and independently ofeach other are hydrogen, cycloalkyl, or alkyl substituted by halogen orhydroxyl; R_(6p) is amino; unsubstituted or substituted alkylamino ordialkylamino; alkoxy; aryl; cycloalkyl; aryloxy; and unsubstituted 5- or6-membered, saturated, partially saturated or unsaturated heterocyclewhich may be condensed containing 1 to 5 nitrogen and/or 1 to 3 sulphur-and/or oxygen atoms; a substituted 5- or 6-membered, saturated,partially saturated or unsaturated heterocycle which may be condensedcontaining 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atomssubstituted by amino, hydroxy, alkoxy, acyloxy carboxy or mercapto;unsubstituted straight chain or branched (C₁₋₂₀)alkyl, (C₂₋₂₀)alkenyl or(C₂₋₂₀)alkinyl, wherein said (C₁₋₂₀)alkyl may be interrupted by S and/orO and said C₂₋₂₀)alkenyl or (C₂₋₂₀)alkinyl be interrupted by N, S,and/or O; once or several times substituted straight chain or branched(C₁₋₂₀)alkyl, (C₂₋₂₀)alkenyl or (C₂₋₂₀)alkinyl, wherein said(C₁₋₂₀)alkyl may be interrupted by S and/or O and said (C₂₋₂₀)alkenyl or(C₂₋₂₀)alkinyl be interrupted by N, S, and/or O, and which issubstituted by hydroxy, by, by alkoxy, by aryloxy, by acyloxy, bycarbamoyloxy, by amino, by alkylamino, by dialkylamino, bytrialkylammonium cation, by acylamino, by ureido, by oximino, by imino,by carboxy, by oxo, by halogen, by nitro, by a carboxylic acidderivative, by a sulphonic acid derivative, by an unsubstituted 5- or6-membered, saturated, partially saturated or unsaturated heterocyclewhich may be condensed containing 1 to 5 nitrogen and/or 1 to 3 sulphur-and/or oxygen atoms; or by a substituted 5- or 6-membered, saturated,partially saturated or unsaturated heterocycle which may be condensedcontaining 1 to 5 nitrogen and/or 1 to 3 sulphur- and/or oxygen atomswhich is substituted by amino, hydroxy, alkoxy, acyloxy, carboxy, ormercapto; and Z_(p) is oxygen or NR_(7p), wherein R_(7p) is as definedfor R_(2p).
 20. A compound of claim 16 of the formula

wherein R_(1p) is hydrogen or CH₂F; and R′_(6p) is (C₁₋₂₀)alkyl,(C₁₋₂₀)alkyl one or two fold substituted by phenyl, phenoxy, amino,hydroxyphenyl, hydroxy, carboxyl, guanidino or nitroguanidino,unsubstituted phenyl or phenyl substituted by acetoxy, or pyrrolidinyl;or a moiety of the formula


21. A compound of claim 16 in the form of a salt and/or in the form of asolvate.
 22. A compound selected from1-[(1-methylhydrazino)iminomethyl]piperazine;1-[(1-ethylhydrazino)iminomethyl]piperazine;1-[(1-allylhydrazino)iminomethyl]piperazine;1-[(1-(4-methoxybenzyl)hydrazino]iminomethyl]piperazine;1-[(1-(3,4,5-trimethoxybenzyl)hydrazino]iminomethyl]piperazine;1-[(1-methylhydrazino)(methylimino)methyl]piperazine;1-[(1-methylhydrazino)(ethylimino)methyl]piperazine;glycin-(4-hydrazinoiminomethyl)piperazide;1-(R)-(amino(4-hydroxyphenyl)acetyl)4-(hydrazinoiminomethyl)piperazine;1,4-bis-(hydrazinoiminomethyl)piperazine; and1-(hydrazinoiminomethyl)-4-[ethylimino)[3-dimethylaminopropyl)amino]methyl]-piperazine.23. (canceled)
 24. A process for the production of a compound of claim16, which comprises a) reacting a compound of the formula

wherein α) R_(b) is hydroxy and R_(c) and R_(d) together are a bond, orβ) R_(d) is hydrogen, a cation, an ester moiety, or a silyl group andR_(b) and R_(c) together are oxo with a compound of the formula


25. (canceled)
 26. A pharmaceutical composition comprising a compound ofclaim 16 in the form of a pharmaceutically acceptable salt or in freeform in association with at least one pharmaceutical carrier or diluent.27. A method of treating microbial diseases which comprisesadministering to a subject in need of such treatment an effective amountof a compound of claim
 16. 28. A process for the production of acompound of claim 16 of the formula

which comprises: a) acylating a compound of the formula

with a compound of the formula

wherein X is a leaving group; or b) reacting a compound of the formula

with a compound of the formula

wherein X is a leaving group.
 29. A compound of the formula

wherein R₅ is hydrogen or an ester moiety and R_(int) is a group of theformula

which is formed by a bond of the terminal amine group of the hydrazinogroup of a compound of claim 22 and wherein the —N— group is substitutedaccording to a compound of claim 22.